key: cord-0947084-tingvt9n
authors: Tammam, Salma N.; El Safy, Sara; Ramadan, Shahenda; Arjune, Sita; Krakor, Eva; Mathur, Sanjay
title: Repurpose but also (nano)-reformulate! The potential role of nanomedicine in the battle against SARS-CoV2
date: 2021-07-20
journal: J Control Release
DOI: 10.1016/j.jconrel.2021.07.028
sha: b1ffb912886cf0459f54506ba854a7ec1cbd58e4
doc_id: 947084
cord_uid: tingvt9n

The coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has taken the world by surprise. To date, a worldwide approved treatment remains lacking and hence in the context of rapid viral spread and the growing need for rapid action, drug repurposing has emerged as one of the frontline strategies in the battle against SARS-CoV2. Repurposed drugs currently being evaluated against COVID-19 either tackle the replication and spread of SARS-CoV2 or they aim at controlling hyper-inflammation and the rampaged immune response in severe disease. In both cases, the target for such drugs resides in the lungs, at least during the period where treatment could still provide substantial clinical benefit to the patient. Yet, most of these drugs are administered systemically, questioning the percentage of administered drug that actually reaches the lung and as a consequence, the distribution of the remainder of the dose to off target sites. Inhalation therapy should allow higher concentrations of the drug in the lungs and lower concentrations systemically, hence providing a stronger, more localized action, with reduced adverse effects. Therefore, the nano-reformulation of the repurposed drugs for inhalation is a promising approach for targeted drug delivery to lungs. In this review, we critically analyze, what nanomedicine could and ought to do in the battle against SARS-CoV2. We start by a brief description of SARS-CoV2 structure and pathogenicity and move on to discuss the current limitations of repurposed antiviral and immune-modulating drugs that are being clinically investigated against COVID-19. This account focuses on how nanomedicine could address limitations of current therapeutics, enhancing the efficacy, specificity and safety of such drugs. With the appearance of new variants of SARS-CoV2 and the potential implication on the efficacy of vaccines and diagnostics, the presence of an effective therapeutic solution is inevitable and could be potentially achieved via nano-reformulation. The presence of an inhaled nano-platform capable of delivering antiviral or immunomodulatory drugs should be available as part of the repertoire in the fight against current and future outbreaks.

Increased human-animal contact, massive animal farming and globalization have facilitated conditions for virus spillover to humans [1, 2] and indeed man-kind has received a number of warnings. The 1918 Spanish Flu (H1N1 virus), severe acute respiratory syndrome coronavirus (SARS-CoV), swine influenza virus and Middle East Respiratory Syndrome (MERS-CoV) all represent viruses of animal origins that have crossed over to humans and represented very formidable foes [3] [4] [5] . Despite multiple warnings, the sequence of events that have started in late 2019 and resulted in the worldwide spread of SARS-CoV2 and its unfortunate multifaceted impact, has taken the world by surprise [6, 7] . A number of cases of "unknown viral pneumonia" related to a local seafood market were reported in Wuhan City, Hubei, China in December 2019 [8] . The underlying reason was rapidly identified as a novel coronavirus (SARS-CoV2) and the resultant respiratory diseases has been named coronavirus disease 2019 (COVID-19) [9] . In March 2020, the COVID-19 outbreak received recognition as a pandemic by the World Health Organization (WHO).

As with other respiratory viruses, transmission is believed to predominantly occur through respiratory droplets (aerosols) [10] , resulting in a plethora of very diverse symptoms. While the main symptoms include fever, a dry cough, dyspnea, myalgia and pneumonia, some patients also reported sore throats, rhinorrhea, headache and hyposomea [11] . Additionally, rectal swabs from infected patients have also tested positive for SARS-CoV2, questioning the possibility of fecal-oral transmission [1, 12] and adding nausea, diarrhea, abdominal pain and hypogeusia to the long list of COVID-19 related symptoms [11, 13] . The diverse nature of symptoms has made it rather difficult to conduct a clinical diagnosis, at least without computer tomography or a specific diagnostic test [14] . Several patients confused COVID-19 for other forms of less serious respiratory [14] or gastrointestinal tract (GIT) illnesses, delaying attempts to seek medical assistance and increasing the risk of diseases transmission. Additionally, a large number of patients remain asymptomatic, despite carrying the virus and hence posing as risk of infection [15] . Coupled with the relatively long incubation periods [15] , the limited availability of approved vaccines [16] and "effective" treatment [14, 17] , it becomes obvious how the current COVID-19 dilemma has come into shape.

With the diseases spreading around the globe, number of infections and related deaths soaring, governments were obliged to enforce border shutdowns, travel restrictions and quarantine [18] . While such measures have significantly dampened the spread of the diseases and temporarily reduced the burden on health systems [19, 20] , prolonged lockdowns are not sustainable and are certainly not a long term solution from both social and economic viewpoints [21] . The measures applied to control the COVID-19 outbreak have already resulted in major socio-economic losses [18, 22] and with the curve of infection rates not flattening, the expected negative impact could be humongous as enforced by lessons learned from the 1918 influenza pandemic [21, 23] . Thus, scientists and researchers all over the world are racing to find cost-effective solutions for early diagnosis and effective treatment of COVID-19 infections. The development and testing of vaccines is still ongoing and the typical timeline for approval of novel drugs can (depending on the substance class) exceed 10 years [24] . An alternative solution is the repurposing of currently approved drugs. Drug repurposing has therefore been on the frontline of strategies used in the battle against COVID-19 [25] . Nanotechnology could be leveraged to provide assistance in the fight against SARS-CoV2, on several levels and one of them is the nano-reformulation of repurposed drugs. The use of nanoparticles (NPs) in drug delivery has reshaped the drug development landscape over the past decades [26] . NPs have been credited for their ability to improve drug solubility, change undesirable pharmacokinetics, allow for the realization of the benefits of new macromolecular therapeutics arising from genomic and proteomic research, and increasing drug localization in target organs and tissues and thus, lowering the systemic toxicity and side effects, i.e., drug targeting [26] . Furthermore, NP size, shape, surface charge and surface chemistry can be modified, facilitating the synthesis of particles with tailored biological properties. For instance, Lammers et al have recently highlighted [27] the promising potential of the reformulation of dexamethasone using nanocarriers. In a similar manner, the reformulation of other drugs that are currently being clinically investigated in COVID-19 is likely to provide new pathways for drug administrations and improved therapeutic outcomes.

Inspired by Professor Kostas Kostarelos plea "Where have all the (nano)scientists gone?" in Nanoscale nights in COVID-19 [4] , in this review, we attempt to show what nanomedicine could and ought to do in the battle against SARS-CoV2. In COVID-19, it has become rather obvious at this point that controlling the diseases requires a cessation of viral progression and control over the rampage immune response that is believed to result in a trail of collateral damage often being indicted for the disease related mortality [28] . We start by a brief description of SARS-CoV2 structure and pathogenicity and move on to discuss the current limitations of repurposed antiviral and immune-modulating drugs that are being clinically investigated in COVID-19. Focus will be shed on how nanomedicine could address limitations of current therapeutics, enhancing the efficacy, specificity and safety of such drugs. 

Several drugs are currently being clinically evaluated against SARS-CoV2, these drugs could be divided into two broad classes; drugs acting on viral components and drugs acting on host cell components. Table  1 provides a list of antiviral drugs that are being clinically evaluated in COVID-19. It is well established that SARS-CoV2 infects respiratory cells in the lungs [12] , making such cells or the associated virions in the lung suitable targets for most of the drugs listed in Table 1 . Up until July 2020, with the exception of ribavirin [47] and recombinant interferons (IFN) [48] , all evaluated drugs were administered systemically. In fact, it is only very recently that inhalation was considered for remdesivir (NCT04480333-July 2020 and NCT045392262-September 2020) and hydroxychloroquine (NCT04497519-August 2020 and NCT04461353-July 2020). The systemic administration therefore stirs up two very pressing points of discussion; how much of the administered drug actually reaches the lung and more specifically the host infected cell and as a consequence, where does the remainder of the dose go? Additionally, where does the drug distribute and what are the resultant off target effects? The answers to these questions become rather obvious by considering the adverse effects observed with these drugs (Table 1) . For instance, GIT side effects are observed with most of the orally administered drugs [49] [50] [51] [52] [53] [54] , in some cases these GIT side effects were severe, leading to the early termination of treatment [49] . In addition to GIT adverse effects, lopinavir/ritonavir also induce hepatic injury given their distribution to the liver following oral administration for instance. The latter is underpinned by lopinavir's low oral bioavailability and its metabolism by the CYP3A4. In fact, one of the main reason for co-administration of ritonavir is to achieve drug concentrations that are high enough to inhibit viral replication while allowing less frequent dosing in HIV patients [55] and in COVID-19 clinical trials (NCT04252885, NCT04255017, NCT04321174). Additionally, lopinavir/ritonavir induce hepatic activity of cytochrome P450 enzymes; CYP2C9, CYP2C19, and CYP1A2 [56] also resulting in multiple drug interactions [49, [57] [58] [59] . The latter becomes rather critical when taking into consideration that patients with severe cases of COVID- 19 While systemic side effects were observed with antiviral drugs targeting viral components (Table 1) , drugs that target host proteins may cause, (depending on administration route and dose) even more undesired side effects, given the wider availability of their target in non-targeted organs [77] . The latter is for instance, rather obvious from the adverse effect profile of chloroquine, hydroxychloroquine and camostat mesliate [53, 54, 76] . In addition to the systemic adverse effects, the low amount of effective drug in the lung might render the use of most systemically administered antivirals in COVID-19 treatment non-conclusive. This is also emphasized by the lack of disease relevant pharmacokinetic trials [89] . Although, currently little is known about the effective drug concentration required to inhibit SARS-CoV2 replication, the exposure of the virus to a low drug concentration in-vivo is a plausible reason for the clinical ineffectiveness observed with antiviral drugs [49, 64] . In fact, following the intravenous administration of remdesivir in two COVID-19 patients, the drug was not detected in bronchoalveolar aspirate [90] . Within the same context, data obtained from MERS patients indicated that the relative concentrations required to inhibit viral replication was higher than actual concentrations detected in sera of patients treated with lopinavir/ritonavir [91, 92] . In a similar manner, camostat mesilate is currently being clinically investigated in COVID-19, where patients are receiving two 100 mg pills, 3 times a day for 5 days (NCT04321096). While investigators are optimistic about the outcomes, based on previous positive in-vitro experiments[40] and results from animal trials [93] , at this point it cannot be guaranteed that enough drug will be distributed to the lungs [94] . Animal trials investigating the efficiency of systemic and inhaled antiviral drugs in influenza have reported similar results [95] . In such cases, the local delivery of drugs directly to the lung would provide a promising approach to deliver higher drug Neuropsychiatric adverse effects [85] concentrations to the site of action while at the same time, minimize toxicity due to off-target distribution and possibly reducing the administered dose [26, 96] , all of which could be potentially achieved with the use of nano and microparticles (MPs).

Upon inhalation of NPs or MPs, their lung deposition and clearance profile depends on their physicochemical properties, as well as the patient's lung anatomy and health state [26, 97] . In the lungs, the airways and the alveoli are lined with pseudostratified epithelium, which is protected by a ciliated mucus layer in the tracheobronchial area [26] . A particle's geometric diameter, density and shape all contribute to its aerodynamic diameter (AD) which greatly decides where the NP deposits in the lung [97] . When inhaled through the mouth, particles with ADs larger than 5μm deposit in the oropharynx and large airways, where they fall prey to mucociliary clearance rather than reaching the lung[98]. Particles with smaller ADs (1-5 μm) deposit deep into the lungs by gravitational sedimentation due to lower air velocity in this region [97, 98] . Finally, smaller NPs tend to be exhaled as they mostly remain suspended in inhaled air [26, 99 , 100] ( Figure 2 ). However, if particles do escape exhalation, they may be deposited in all regions of the respiratory tract by diffusion [98] . In case their lung delivery is required, attempts to enhance NP lung deposition include nebulization or incorporation into larger particles [26, 101] . While targeting of most lung regions seems possible with NPs and/or MPs, the important questions is; where is the NP/MP deposition required for treatment of COVID-19? Are there any specific disease related changes in the lung physiology that could be exploited for better drug targeting to the needed site? [115] [116] [117] . These studies should serve as guidelines for the formulation of mucus penetrating NPs [118, 119] . CoVs heavily glycolyzed S proteins endow mucus penetrating properties, which indicates that PEGylation of NPs; the conjugation of polyethylene glycol onto the surface of the NP could endow similar favorable attributes [118] [119] [120] .

Another possible approach to increase the NP residence time in the nose would be binding to cilia. This would be rather interesting in COVID-19 since the virus is believed to gain access through ciliated cells attributed to their very high expression of ACE2 receptors [103] . In such case, the NP would require functionalization with a cilia binding ligand and loading with APN01 ( Figure 3A) . Several receptors have been reported to exist on cilia of the differentiated human airway and nasal epithelium[109, [121] [122] [123] [124] and hence could be used to facilitate NP active binding to cilia. An interesting observation is that most of these receptors when stimulated with appropriate ligands, trigger a response that could result in pathogen clearance. For instance, upon the stimulation of the sensory bitter taste receptors (T2R) an increase in concentration of intracellular calcium occurs, which culminates in increased ciliary beat frequency, providing a defensive mechanism for the elimination of potential pathogens [125] . More specifically, Lee et al. demonstrated that stimulation of T2R38 (one of the T2R receptors which is expressed in motile cilia lining the sino-nasal cavity) results in nitric oxide production [126] , which demonstrated antiviral effects towards SARS-CoV [127] . The latter reveals a possible synergistic action of APN01 loaded cilia targeted NPs in the SARS-CoV2 prophylaxis. To the best of our knowledge, to date, the formulation of NPs capable of actively binding to motile cilia in the nasal cavity or the respiratory system has not been reported. However, Pala et al. synthesized nano-drug delivery systems loaded with fenoldopam capable of binding to primary cilia for the treatment of ciliopathy related vascular hypertension [128] . Dopaminereceptor type-5 (DR-5) is largely expressed in cilia. Hence, the authors speculated and elegantly demonstrated that DR-5 labelled NPs could be used to functionalize NPs for cilia targeting [128] . In the case of motile cilia, cilia beating movement might make it harder for the NPs to actually make sufficient contact with the receptors. Viral particles are bioengineered NPs [4] . If these naturally engineered nano-pathogens could deposit onto beating cilia, why would not the man-made nanomedicines behave similarly? On this note, irrespective to the active interaction with cilia, NP deposition on motile cilia might also offer an added advantage. By adjusting the physicochemical properties of the NPs, an increase in cilia beat frequency could also be obtained; anionic NPs with diameters larger than 300 nm have shown to increase cilia beat frequency upon their deposition, also possibly resulting in enhanced viral clearance [129] . This relatively large particle size, would also limit NP absorption and their translocation to the brain through the olfactory pathways[109] limiting systemic toxicity and increasing residence time in the nasal cavity.

In the symptomatic phases of the diseases, from a drug delivery perspective, delivering the drugs to the upper and conducting airways or deep into the alveolar region would help prevent disease progression and deterioration of patient health, hence reducing mortality rates. To do so, antiviral drug encapsulation into particles with suitable ADs (1-5μM) would be necessary [130] . In addition to the suitable AD, these particles should be suited to drug physicochemical properties to allow for a high encapsulation efficiency (EE) of drug, a suitable drug release profile and more importantly the preservation of drug functionality [26] . Since most of the drugs that are currently being clinically investigated in COVID-19 therapy are repurposed drugs, a number of nano-formulations although not for therapy of COVID-19, have been reported ( Table 2 ) and meet most of the aforementioned perquisites of a suitable carrier system. To date, nano-formulations containing recombinant human ACE2 (APN01) have not been reported. APN01 is a water soluble bulky molecule [131] and hence would be best encapsulated into hydrophilic polymeric systems via formulation methods that are devoid of heat and the use of organic solvents [106, 132] . Alternatively, silica NPs could also be utilized for the encapsulation of APN01 or other hydrophilic drugs. In this case, APN01 is allowed to diffuse into prefabricated silica NPs under nondenaturing conditions [133] . Only very recently (September 2020), has remdesivir been nanoreformulated [134] . This nano-formulation is a PEGylated dendrimer that allows a sustained release of remdesivir allowing less frequent dosing [134] . Remdesivir is a low molecular weight compound with low water solubility and higher solubility in ethanol [135] and dimethyl sulfoxide (DMSO) [136] . Accordingly, when considering alternative options for its encapsulation into nanocarriers, formulation of polymeric NPs by nanoprecipitation using ethanol soluble biodegradable polymers could offer a suitable encapsulation approach [132, 137] , or mesoporous silica capsules [138] . Alternatively, other drugs have been encapsulated into chitosan NPs by a modified form of the inotropic gelation method, where the drugs were incorporated through the use of DMSO [139] , also offering a possible means for the nanoencapsulation of remdesivir. 

While most of the particles listed in Table 2 show a decent ability to encapsulate antiviral drugs, their relatively small size would render them not suitable for deposition in the lung following inhalation [26, 100] at least without breath coordination [26] . Notwithstanding, if they do deposit in the conducting airways or deeper in the lung, this small size would increase their interaction with epithelial cells allowing for the delivery of higher drug concentrations in the target cell cytosol [26, 186] . This smaller size would also reduce particle phagocytosis which is significant for particles of geometric diameter ranging between 1 μm -2 μm and decreases for smaller particles[100, 130, 186, 187] . But is evading phagocytosis by pulmonary macrophages really beneficial? Early on at the beginning of the pandemic, the ability of SARS-CoV2 to infect macrophages was debatable. With time it has been speculated [188] , then demonstrated by autopsy and pathological postmortem investigation of two patients [189] . More recently, it has become rather obvious that SARS-CoV2 infects monocytes and macrophages stimulating cytokine release and the up-regulation of M2-type molecules [190] . However, the ability of the virus to replicate 10 ----Silver NP [185] 2 18#

*Drug content w/w% # calculated as % from total mass based on Energy Dispersive X-Ray (EDX) analysis NP: Nanoparticle, PCL: poly caprolactone, PLA: poly lactic acid , PLGA: poly lactic co-glycolic acid, SLN: solid lipid nanoparticles, J o u r n a l P r e -p r o o f inside these phagocytic cells remains elusive [190] .With this information on hand, it seems that the deposition of larger NPs deep into the lung would be preferred. The latter could be achieved through nebulization [191] . The use of nebulizers is common in hospital setting for the treatment of respiratory diseases and is feasible for elderly patients[111] that are more prone to serious cases of COVID-19. When NP suspensions are nebulized, NPs deposit in the lung as a function of the AD of the atomized suspension droplets. It is however important to ensure that the NP size and surface properties do not change upon storage in solution, nor does a significant drug release occur before administration. Additionally, it would be necessary to optimize NP suspension concentration to avoid particle aggregation [192] . Another possible approach is the incorporation of NPs in larger MPs that dissolve releasing smaller NPs once in contact with fluids at the site of deposition, or similarly adsorb them onto water soluble carriers of suitable ADs ( Figure 3B) [101 , 193] . In such case, the NPs would be stored in dry state and hence ensure that the concerns observed with nebulization are somewhat limited [194] . The use of dry powder inhalers (DPI) has been in deed utilized for the delivery of NPs [195] . Notwithstanding, MPs have also been used for drug delivery to the lung following inhalation [196] . Table 3 provides examples form literature by which small NP lung deposition was enhanced by nebulization or through the incorporation into larger particles for administration in dry form for local drug delivery to the lung.

Diseases Particle type Therapeutic agent

Asthma / COPD/airw ay inflammatio n SLN and NLC [197] Beclomethasone dipropionate 0. 16 

Once deposited in the lungs, approaches to enhance interaction with target cells would be desirable. ACE2 receptor is expressed on ciliated bronchial cells, among others [50] . Concomitantly, SARS-CoV2 has been reported to infect bronchial and bronchiolar mucosa [215] . In such case, if NPs that have been designed to deposit in the conducting airways were actively modified to bind to ACE2 receptor, theoretically a more specific drug delivery could be achieved. Not dependent on the loaded drug, these particles would also compete with the virions over the available ACE2 receptors ( Figure 3C ). The functionalization of NPs with angiotensin II has been previously reported [216] and would be expected to increase NP interaction with ACE2 receptors and enhance NP internalization. The latter is based on the reported ability of angiotensin II to induce ACE2 internalization and degradation into lysosome [217] . While there is currently no data available indicating whether NP bound angiotensin II could be metabolized by ACE2 or type 1 angiotensin II receptor (AT1R), care has to be taken however with the exogenous administration of angiotensin II in any form, since the enhancement of angiotensin II signaling and the attenuation of ACE2 activity are believed to be a primary driver of COVID-19 ARDS [218, 219] . Hence, other ACE2 binding ligands might more appropriately serve the task, or the co-administration of AT1R blockers such as losartan [220] . Within this context, losartan is currently being clinically investigated in COVID-19 (NCT04335123). Alternatively, cationic polyamidoamine dendrimer NPs have also been shown to bind to ACE2 receptors in the lung. However, these particles have also been reported to induce lung injury via deregulation of the renin-angiotensin system [221] .

Drug delivery to the alveoli would also be required in severe cases of COVID-19. SARS-CoV2 was detected in type I and II pneumocytes in infected macaques [215] and in humans is believed to mainly infect type II cells [222] . Type II pneumocytes are responsible for the generation of pulmonary surfactant which is crucial for reduction of surface tension in the lung [223] . SARS-CoV2 mediated damage to type II cells drastically reduces pulmonary surfactant production and its secretion to the alveolar space [224] . As a consequence, atelectasis and the perturbation of the air-liquid-interphase occur [224] . On top of being critical to one's survival, these changes to the lung structure and function also complicate NP delivery to infected pneumocytes. Thorely et al. demonstrated the ability of human alveolar type I cells to internalize 50-100 nm NPs [186] . More importantly, the authors reported that prior to cell internalization these NPs were opsonized by surfactant proteins and such opsonization mediated their cellular internalization [186] . The alterations that occur in surfactant quantity and make-up may therefore complicate NP uptake by alveolar cells in COVID-19 lungs. In ARDS, relative to healthy surfactant, an isoniazid and pyrazinamide PLGA NP [191] Rifampicin, isoniazid and pyrazinamide 80% reduction in the total phospholipid content is observed in addition to massive reduction in surfactant protein A (SP-A) content [225] [226] [227] . Both phospholipids and pulmonary surfactant proteins, including SP-A, present a significant portion of the inhaled NP corona and are believed to mediate NP uptake by macrophages and/or alveolar cells [186, 228, 229] . In this context, utilizing a combination of NP coating with pulmonary surfactant in addition to active targeting would enhance NP delivery to infected cells.

Backer et al. elegantly demonstrated that while the presence of a pulmonary surfactant on the outer shell of RNA loaded NPs significantly lowered their cellular internalization, it surprisingly increased RNA expression levels. The authors speculated that this increase in RNA expression was the result of reduced RNA leakage and modulation of intracellular trafficking by the surfactant coat. Interestingly, upon incorporation of folate on the outer surfactant shell, a massive increase in NP internalization by folate receptor expressing cells was observed, which was also complimented by a further increase in RNA expression [230] . Particle tagging with SP-A should also facilitate NP internalization. A number of SP-A binding receptors have been identified on the pneumocyte membrane [231] [232] [233] [234] . Among which CKAP4/P63 and BP55 facilities SP-A derived receptor-mediated endocytosis in type II cells [234] [235] [236] [237] . Indeed, SP-A mediated liposome uptake in freshly isolated type II pneumocytes via a receptor-mediated endocytosis process involving BP55 has been reported [234] . Type II pneumocytes also express the scavenger receptor class B type 1 (SR-B1), which is specific to high-density lipoprotein (HDL) [238] .

Luthi et al. synthesized HDL-like NPs using gold NPs as a core template which was then decorated with phospholipids and apolipoprotein A-I [239] . Although not in pneumocytes, but these HDL like NPs demonstrated high functional ability to bind SR-B1 [240, 241] . Also not for pneumocyte targeting HDLmimetic poly lactic co-glycolic acid (PLGA) nanoparticles have also been synthesized [242] and could be similarly employed for targeted drug delivery to infected type II cells ( Figure 3D ). But is drug delivery into infected alveoli really necessary? Or is drug delivery with-in their vicinity sufficient? Especially if coupled to approaches that would increase their resident time in the lungs and also if antiviral delivery to phagocytic cells is required. This enhanced residence would provide ample time for drug release, providing local high concentrations of antiviral drugs. Similar to SARS-CoV, the diffused alveolar damage observed in COVID-19 patients is accompanied with fibrin rich hyaline membranes [243] . Fibrin clots in the alveoli are also prominent, this is in addition to collagen accumulation which all contribute to the development of a fibrotic lung state [223, 224, [243] [244] [245] . Approaches to enhance NP residence would either exploit the intrinsic ability of the NP building materials to bind one of the aforementioned targets or their active modification with binding ligands. To exemplify the former, we have recently demonstrated the intrinsic collagen binding ability of chitosan NPs and have in fact utilized these NPs for drug delivery to fibrotic livers as function of such binding [246, 247] . Analogously, chitosan NPs possessing the required physicochemical properties to deposit deep into the lung should bind to fibrotic regions of the lung showing lower clearance and prolonged residence time as a function of collagen binding ( Figure 3E ). Fibrin and/or fibrinogen binding NPs have been explored for tumor targeting [248] . The leaky vessels to which "enhanced permeation" (EP in EPR) is attributed to in NP cancer targeting, are also responsible for the blood clotting products that bedeck the walls of tumor vessels and the interstitial spaces [248] . Within this context, CREKA (Cys-Arg-Glu-Lys-Ala) coated iron oxide NPs have shown specific affinity for tumor vessels endowed by the fibrin-fibrinogen binding properties of the CREKA peptide [249] . Other fibrin-fibrinogen binding peptides have been reported in literature [250, 251] and could in fact be utilized for similar purposes in COVID-19 patients following inhalation. While J o u r n a l P r e -p r o o f not related to antiviral effects, these clot targeting particles could also be loaded with thrombolytic agents and hence help mitigate one of the very significant reasons for COVID-19 associated mortality.

While it is logical to question the suitability of inhalation therapy in COVID-19, particularly for patients with severe diseases and those on mechanical ventilation, the use of aerosol therapy during mechanical ventilation is expanding. Delivery of therapeutic agents by inhalation has seen increasing applications for many respiratory diseases, including asthma, chronic obstructive pulmonary disease (COPD), allergies, and influenza [98] . Pressurized metered-dose inhalers (pMDIs) and nebulizers are commonly employed in intensive care units even in mechanically ventilated patients [252] . 

J o u r n a l P r e -p r o o f Activation of the innate and adaptive immune responses occurs in reaction to SARS-CoV2 infection. A well-coordinated immune response is indeed required for defense against viral infection and has proven efficient in SARS-CoV2 eradication in the majority of COVID-19 patients. In a small subset of unfortunate patients, excessive and deregulated host immune defenses have resulted in harmful tissue damage [219] . Recent data from clinical trials demonstrate that at around one week post infection, patient health state is mainly incapacitated by immunopathological events as opposed to the virus itself (NCT04381936) [27] . To address the enraged host immune defenses, a number of immune-modulating drugs are currently being clinically investigated. Table 4 provides a list of these drugs, their molecular targets and reported side effects. Before addressing the possible advantages endowed by the nanoreformulation of these drugs, a description of SARS-CoV2 induced immunopathology is warranted. Based on current data from COVID-19 patients and based on lessons learned from SARS-CoV and MERS-CoV, a number of reports elegantly attempted to delineate the SARS-CoV2 immunopathology [219, 222, [253] [254] [255] [256] [257] . However, in the current situation, where the exact underlying pathways and actions indicted of such detrimental events are not fully understood, here, we choose to tackle SARS-CoV2 induced immunopathology from a treatment perspective and hence will only provide a brief overview of the major pathways and components implicated in SARS-CoV2 immune mediated damage, to further justify the reason for and the means of nano-reformulation of the repurposed immunemodulating drugs. 

Severe cases of COVID-19 are characterized by a state of hypercytokinemia or a "cytokine storm" [257] . The cytokine storm commences by the activation of the innate immunity upon SARS-CoV2 infection to epithelial cells. Infected epithelial cells, innate immune and endothelial cells release a multitude of cytokines with aim of halting viral replication and recruiting effector cells to eliminate infected ones. Delayed IFN response (among other factors) results in viral persistence and the consequent sustained release of cytokines along with the immune signaling, trigger a secondary wave of cytokine release ultimately resulting in a cytokine storm [255, 256] . Molecules such as interleukin (IL) IL-6, IL-1β, IL-2, IL-7, IL-10, in addition to, IFN-γ, monocyte chemo-attractant protein (MCP-1), macrophage inflammatory protein (MIP-1α) and tumor necrosis factor (TNF-α) are elevated in critical cases and are associated with SARS-CoV2 mediated damage [222, 340] . Immunomodulatory drugs that are currently being repurposed for COVID-19 therapy either target the produced cytokines and/or chemokines, or the underlying pathway(s) that result in their uncontrolled release. (Figure 4) . Increased degradation of IκB has been reported to occur upon interaction of CoV S-protein with host cell. IκB is an inhibitory protein which under normal conditions resides in the cytoplasm. Through a sequence of events, the degradation of IκB results in the activation and nuclear translocation of nuclear factor (NF-κB) resulting in the transcription of a multiplicity of genes encoding several inflammatory chemokines and cytokines (Figure 4(i) ), including those of the TNF-α/IL-6 axis [29, 253, 341, 342] . IL-6 in particular presents a rather interesting cytokine and a therapeutic target. Elevated IL-6 levels are believed to be predictors for diseases severity and the need for mechanical ventilation [343] [344] [345] . In the host cell, IL-6 promotes the downstream activation of Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling (Figure 4(ii) ), which in turn results in further production of IL-6 [219] . Additionally, SARS-CoV2 infection results in the down-regulation of ACE2 receptors on host cells, thus resulting in overproduction of angiotensin II [222] . Indeed, increased angiotensin II plasma levels in SARS-CoV2 infected patients were linearly associated to viral load and lung damage [346] . This increased angiotensin II binds to AT1R, resulting in the activation of JAK/STAT signaling pathway and once more, the overproduction of IL-6 (Figure 4(iii) ). The Angiotensin II/AT1 receptor axis is also implicated in further activation of the NF-κB pathway resulting in a positive feedback loop increasing inflammatory cytokine production (Figure 4(iv) ). It therefore seems rather logical that IL-6 and IL-6 receptor antibodies (such as sarilumab, tocilizumab, sirukumab, siltuximab and olokizumab), drugs reducing the expression or nuclear import of NF-κB (such as CD24Fc and selinoxor) and JAK inhibitors (such as tofacitinib, fedratinib, TD-0903 and ruxolitinib) have all been repurposed for COVID-19 therapy ( Table  4 ). 

In addition to other cytokines, IL-6 produced by the infected host cell, in combination with the released virions and viral components, activate and recruit immune cells [222] . Indeed, IL-6 synergizes with TNFα and IL-1β, up-regulating trypsin expression and activating matrix metalloproteinase resulting in the breakdown of the basal membrane, increased tissue permeability and immune cell recruitment [347] (Figure 4(v) ). Macrophage activation syndrome (MAS) is a critical consequence and a contributor to such events (Figure 4(vi) ).The latter is underpinned by data from analysis of bronchoalveolar lavage fluid obtained from COVID-19 patients with severe disease, that show an abundance of proinflammatory monocyte-derived macrophages [348] , with a concomitant depletion of tissue-resident alveolar macrophages [348, 349] . The latter is potentiated via the action of granulocyte macrophage-colony stimulating factor (GM-CSF). In healthy lungs, GM-CSF is normally released from type II alveolar cells and is necessary for surfactant homeostasis and alveolar macrophage development. In severe inflammatory states, GM-CSF production is up regulated by type II epithelial cells and monocyte-derived macrophages. Monocytes differentiation into the pro-inflammatory phenotype is achieved though activation of the JAK/STAT pathway resulting in a positive feedback loop of GM-CSF production that results in further perpetuation of the inflammatory milieu [254, 350, 351] . These macrophages in turn result in increased production of IL-6, IL-7, TNF-α and also chemokine ligands CCL, CCL2, CCL3 and CXC-chemokine ligand 10 (CXCL10) [254, 352] , resulting in an inflammatory cytokine-chemokine cocktail. For such reasons, therapeutic compounds acting through the inhibition of TNF-α (adalimumab), IL-1 (anakinra and canakinumab), GM-CSF (mavrilimumab, gimsilumab, and TJ003234) have also been repurposed and are being clinically evaluated in COVID-19 therapy ( Table 4) . Bevacizumab a vascular endothelial growth factor (VEGF) antibody, is also being evaluated in COVID-19 ( Table 4 ). The downregulation of ACE2 receptor by SARS-CoV2 is believed to increase VEGF expression which are considered key factors in acute lung injury and ARDS due to their ability to increase vascular leakiness and permeability [353] . Table 4 ). Activation of C3 and the complement activation fragment anaphylatoxin C5a in particular [354, 355] , are major contributors, since the pharmacological blockade of their receptors attenuated pulmonary inflammation and led to decreased viral replication in infected lungs [356] . In SARS-CoV2 infection, complement activation, indicated by an increase in C3a in the lung and C5a in serum was reported in patients with severe COVID-19 [357] . More importantly, treatment with anti-C5a antibody resulted in immediate clinical improvement [357] . C3 inhibitors might be more effective, but have yet to be approved. This might be attributed to the upstream positioning of C3 signaling in the innate immune cascade. In fact, C3 inhibition could simultaneously block C3a and C5a generation, as well as intrapulmonary C3 activation and IL-6 release from alveolar macrophages, or other cells that express C3a receptors (C3aRs) and/or C5a receptors (C5aRs), thereby ameliorating lung injury [357] .

The use of immunomodulatory drugs might offer a safe haven from the SARS-CoV2 induced hyper inflammation. However, several critical issues have to be considered, the first of which is the treatment timing. Early treatment might adversely affect viral clearance. For such reason, immunomodulatory therapy should not serve as the first line of treatment and the use of antiviral drugs ( Table 1) should precede such modalities [358] . In that sense, their effectiveness could be enhanced by nano-reformulation for inhalation therapy. The broad ablation of IL-6 at very early stages of the infection may result in delayed antiviral antibody responses [359] . Within the same framework, treatment modalities employing IFN are used in early diseases stages to halt viral replication (please see Table 1 ), however, IFN ʎ antibodies (Emapalumab -see Table 4 ) are also being clinically evaluated in severe disease. The same would apply to other cytokines and chemokines. For instance, GM-CSF is beneficial for maintaining alveolar macrophage function which is necessary during viral assault in early disease and indeed, J o u r n a l P r e -p r o o f recombinant inhaled GM-CSF is currently in phase IV studies in patients with COVID-19 infection and acute hypoxic respiratory failure (NCT04326920). At a later stage however, neutralizing excessive GM-CSF may attenuate the cytokine storm and the consequent lung destruction. Notwithstanding, early (but not too early) immunomodulatory intervention, afore the onset of respiratory failure, may prevent poor outcomes. Once inflammation is no longer lung central, the "window of opportunity" for immunomodulatory interventions as referred to by Mehta et al. might have already been missed, and patients then spiral down into an abyss of deterioration, during which initiation of treatment would probably not be of substantial clinical benefit [279] . Early identification of patients with potential deregulated immune-responses would therefore allow for better targeting of such "window of opportunity" and hence the identification of robust predictive biomarkers for hyper inflammation represents a holy grail for COVID-19 research [360] . While such biomarkers are yet to be discovered, in the meantime, avoiding the side effects of the generalized systemic inhibition of the implicated immune players seems like a less tortuous route, at least when visioned from the context of nano-reformulation. Most of the cytokines (and/or the implicated players) that are the focus of the investigated drugs are pleiotropic molecules with diverse multifaceted functions including roles in tissue homoeostasis, hematopoiesis, host defenses, epithelial repair among others [361, 362] and their generalized inhibition would not result in positive outcomes. For instance, the generalized blockade of IL-6 could result in a rapid suppression of C-reactive protein and fever, complicating the detection of secondary infection or even viral relapse. This could also serve as a false reassurance for the efficacy of the therapeutic agent, since a reduction in C-reactive protein and fever would be regarded as a clinically positive outcome [279] . So far most immunomodulatory drugs assessed in COVID-19 clinical trials are being administered either orally, subcutaneously and intravenously (Table 4 ). This once more spikes the same questions discussed in the previous section of this review; how much of the administered drug actually reaches the lung and as a consequence, where does the remainder of the dose go? Needless to say, elevated IL-6 (among others) plasma levels are observed in critical cases of COVID-19 [363] , but it all initially starts in the lungs [279, 364] . Would not inhalation therapy allow higher concentrations of the drug at the sight of inflammation, lower concentrations systemically and hence a stronger, more localized action, with reduced adverse effects? We therefore consider the nano-reformulation of the immunomodulatory drugs for inhalation therapy a viable approach to enhance the drug efficacy with the potential of high specific surface area in nanocarriers or nanosized capsules. This is backed up by the urgent appeal from the International Society for Aerosols in Medicine (ISAM), urging governments and decision makers to consider the inhaled route for therapy of COVID-19 [365] and by the adverse effect profile of utilized systemically administered drugs ( Table 4 ). In fact, a nebulized solution of the JAK inhibitor TD-0903 is currently being clinically evaluated in COVID-19 (NCT04402866). In its inhaled form, TD-0903 shows higher lung selectivity and reduced systemic distribution [366] . In this case, its solubility and rather stable nature has enabled its nebulization, but could the same be applied to other drugs? Or would their nano-reformulation offer added advantages? For the latter to materialize it is necessary to point out what would be expected of the carrier system in this case? The critical points that need to be addressed through concerted efforts include, deep lung deposition, preservation of the functionality of the loaded therapeutic molecule and possibly a prolonged residence time and/or sustained drug release. In a similar manner to antiviral drugs, the reformulation of the immunomodulatory drugs into NPs and MPs could facilitate their deposition deep into the lung (Figures 2 and 3) . This would however mandate the optimization of the particle's AD as discussed in the previous section. But other than allocating in the lung, would targeting a specific cell be required? Should active targeting be employed? While theoretically the modification of the NPs with J o u r n a l P r e -p r o o f targeting ligands would be expected to increase their allocation in the target cell [26] , in this case the identity of the target cell however remains elusive. Most of the intracellular pathways implicated in the overexpression of the inflammatory cytokines and chemokines are present in epithelium, endothelial and immune cells of the lungs and hence delivering drugs (that act on intracellular targets) to a specific cell would complicate the formulation procedure without much added benefit. At the same time, inflammatory cytokines and chemokines are abundant in the extracellular compartment in the vicinity of the alveolar space and hence intracellular delivery of the drugs would also not be required. One can therefore speculate, that excessive attempts of targeting might not offer substantial benefit and believe that efforts invested in maintaining high drug concentrations in the lung might be of more fruitful outcome. This is in addition to simpler formulation, upscaling and approval procedures. The latter being dependent on the fact that the drugs employed are repurposed drugs that have already been approved for other indications.

Approaches that enhance NP and MP residence deep in the lung and reduce their clearance should enable a sustained therapeutic effect. To that end, modalities that exploit changes associated to lung physiology in COVID-19 as discussed earlier would be rather interesting. Particles that show binding to the ECM components such as collagen for instance [246, 247] should serve such target. More importantly however, is the ability of the NPs to preserve the functionality of the loaded molecule. With the exception to a number of low molecular weight compounds, most of the employed therapeutics are protein drugs, more specifically antibodies ( Table 5 ) and hence care has to be taken during formulation to avoid functionality losses [132] . When considering the protein therapeutics in Table 5 , to date, to the best of our knowledge, only nano-formulations for bevacizumab [367] [368] [369] [370] [371] [372] [373] and tocilizumab [374] , an IL-6 antibody [375] and an IL-1 receptor antagonist [376, 377] have been reported. In such cases the antibodies were either tagged to the NP surface or encapsulated. Tagging to the surface was achieved either by allowing the antibodies to adsorb to the NP surface [374] or by covalent linking using mild conditions [371, 372] . While extremely simple in principle, surface adsorption would result in an uncontrolled density and orientation of antibody on the surface of the NPs [378] , possibly hindering binding to the target. Additionally, when exposed to a complex matrix such as lung surfactant or serum, uncontrolled displacement of the adsorbed antibody with other proteins that are of higher affinity or abundance might occur [132] . Covalent linking of the antibodies addresses the aforementioned limitations. The use of 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC) is in fact a very popular approach to do so[101, 371, 372, 375] . EDC is an amine carboxyl linker and is usually used to link the antibody's terminal carboxyl groups to NP surface amines[101]. This would limit the choice of NPs to those with amine groups or would require functionalization of the NP surface with the same. Alternatively, encapsulation of the antibodies would also sever the purpose. In fact, the encapsulation as opposed to surface tagging might bestow additive protection to the loaded macromolecules [379] . Notwithstanding, the correct excipients and formulation approach are necessary to avoid losses of functionality. For instance, bevacizumab has been loaded into PLGA NPs by the double emulsion solvent evaporation technique with an EE% ranging between 67-69% [368, 370] . While it is true that the protein is initially dissolved in an aqueous solvent, during the primary emulsion step, proteins partitioning at the water-organic solvent interface would be susceptible to denaturation and aggregation [380] . Indeed, Sousa et al. [368] clearly demonstrated the aggregation of bevacizumab upon encapsulation into PLGA NPs by the double emulsion solvent evaporation technique. This was demonstrated by the occurrence of intermolecular β-sheets upon investigation of the secondary structure of the protein pre and post loading into NPs. In addition to being therapeutically inactive, the resultant aggregates of denatured proteins could result in immunogenicity or toxicity [381, 382] . The addition of bovine serum albumin (BSA) to the inner water phase could avoid such aggregation [383] . Due J o u r n a l P r e -p r o o f to their surface active properties the added BSA molecules partition at the interface protecting bevacizumab against entrapment stresses [383] . While it is plausible for the large BSA molecules to reduce loading of therapeutic antibody, BSA surface activity could compensate for the latter since it would result in reduced drug leakage and formation of more stable emulsions. Notwithstanding, while BSA has stabilized bevacizumab [383] and could be expected to stabilize other antibodies (which are the majority of COVID-19 investigated drugs), care has to be taken since albumins have on occasions failed to stabilize other the loaded proteins [384] . Another factor to consider with PLGA NPs is the autocatalytic degradation of the ester backbone, resulting in the acidification within the NP milieu. This acidification could lead to the degradation of the loaded protein [132] and hence the co-encapsulation of magnesium hydroxide could help neutralize this acidic pH [385] . Alternatively, chitosan NPs prepared via inotropic gelation might offer a simpler approach for the encapsulation of sensitive macromolecules. Organic solvents and heat are not employed in ionotropic gelation where the incorporation of therapeutic proteins occurs via mild electrostatic interactions in aqueous, physiological conditions [132] . In fact, for protein delivery, chitosan NPs has shown an ability to stabilize the loaded protein, provide a high EE, reduced burst, and provide a sustained release of active macromolecular drugs [246, 386, 387] . In addition, the use of chitosan could allow for an increased residence time. The presence of intra-alveolar fibrinous exudates and loose interstitial fibrosis in lungs of severe COVID-19 patients [244] , spikes interest as to whether the collagen binding ability of chitosan [246, 247] could be exploited for prolonged drug availability at their site of action. Moreover, the presence of surface amines, enables facile functionalization of these NPs by various targeting ligands via the use of commercially available crosslinkers under mild conditions [388] . These targeting ligands would not be intended to target the NPs to a specific cell but to allow for an increased residence time.

These "increased residence" strategies could also be used for the delivery of low molecular weight compounds. In fact, several of the low molecular weight immunomodulatory compounds that are being clinically evaluated in COVID-19 have been nano-scaled ( Table 5) . Despite being repurposed, some of the clinically evaluated drugs to date have not been formulated in the "nano" form. Selinexor, duvelisib, ruxolitinib, and ciclesonide for instance all show poor water solubility but at the same time show relatively high solubility in ethanol[389, 390] and hence could be incorporated into hydrophobic polymeric NPs using the nanoprecipitation technique [132] . Silica NPs could also be used for the loading of hydrophobic drugs [391] , these particles offer controlled release advantages given the possibility of the use of gate keepers that control drug diffusion out of the pores [392] . On the other hand, fedratinib and acalabrutinib show pH dependent solubility [393] [394] [395] and could hence be encapsulated in liposomal carriers, hydrophilic polymeric NPs or hydrophobic polymeric NPs via double emulsion based approaches [132] . Special considerations in this case have to be taken to avoid low EE%, rapid drug leakage and burst release [132] .

More recently, focus has been shifted to a cocktail of immunomodulatory drugs as opposed to the use of a single drug [219, 340, 396, 397] . This is due to the activation of numerous redundant pathways, requiring simultaneous action to exert synergic or additive effects [219] . In that sense, nano-reformulation might also offer added benefits. The ability of a particular carrier system to deposit in the lung, should allow multiple therapeutic agents to co-localize in the same region and hence increasing the chance of synergetic action. However, within the same context, and taking into consideration the existence of a MAS-like state in COVID-19, should not the use of corticosteroids be prioritized [27, 364] ? Corticosteroids are well known cytokine suppressors, anti-edematous and anti-fibrotic agents [27] , their J o u r n a l P r e -p r o o f use in COVID-19 however remains debatable with evidence to both support [398, 399] and advise against [400] their use. Interestingly, the main concern for advising against their use is the delayed (or reduced, depending on time of treatment) antiviral response, which is also a concern for other immunomodulatory drugs and is actually emphasized when these drugs are used in a cocktail form. These antibody cocktails however, come at a higher cost and since they have not been in use as long as other "tried and tested" drugs such as dexamethasone, budesonide and prednisolone for instance, they come with a unexplored risk and a set of adverse effects [27] . While systemic corticosteroids are being clinically evaluated in COVID-19 (NCT04381936, NCT04445506, NCT04519385, NCT04325061, NCT04513184), inhaled corticosteroids are also being evaluated (NCT04416399, NCT04355637, NCT04193878, NCT04377711 and NCT04330586). The inhaled form should offer less systemic side effects, and since they have been on the market for decades now, offer a shorter route from the perspective of necessary approvals. Notwithstanding, most of these inhaled formulations have been employed in the treatment of asthma and COPD and mainly aim at targeting the bronchi and conducting airways [401] and require multiple treatments per day. It is therefore questionable whether in their current from, these drugs could reach the alveoli. It could be postulated that nebulized free corticosteroids may not achieve sufficient alveolar drug concentrations in COVID-19 infection based on the notion that nebulized antibiotics are not effective in bacterial pneumonia [402] . In that sense, the nano-reformulation of these drugs, might allow enhanced drug delivery deep into the lung and possibly provide a sustained release of drug, hence requiring less frequent dosing. The latter is emphasized by the success of Arikayce, an inhaled liposomal suspension of amikacin which has shown superior ability in depositing deep in the lung and targeting of alveolar macrophages [403] . Several nanocarriers have been successfully loaded with corticosteroids ( Table 5) , among which several have been employed in inhalation therapy ( Table 3) .

Should not these systems be expedited for use in COVID-19? One last note, corticosteroids, specifically ciclesonide and mometasone were able to suppress SARS-CoV-2 replication in -vitro to a similar degree as lopinavir. The target for ciclesonide seems to be the nonstructural protein 15 (NSP15) [404] , which might provide added reason for the nano-reformulation of such drugs.

J o u r n a l P r e -p r o o f [371] 190 38 Chitosan NPs [373] 78.5 67.6

Leronlimab Soluble at low pH [418] 615.62 g/mol ---------

Sparingly soluble [178] 516 J o u r n a l P r e -p r o o f

While this account strongly advocates the nano-reformulation of both antiviral and immunomodulating drugs for inhalation therapy, it is also noteworthy that in some cases the systemic administration of these nano-drugs might be warranted. In case the proposed window of opportunity has been missed and that inflammation is no longer lung centralized, the ability to increase immunosuppressive drug concentrations in the target immune cell would be highly needed. In that sense, relying on the consensus that intravenously administered NPs with specific physicochemical properties accumulate in macrophages [26] , drug targeting to phagocyte rich myeloid and lymphoid tissues becomes possible [27] . Systemic administration might also be useful for drugs with targets located in endothelial cells. These cells have been central orchestrators of cytokine amplification during other respiratory virus infections [474] . Fingolimod is a sphingosine-1-phosphate receptor regulator (FTY720) and has proven rather useful in multiple sclerosis [328] . Fingolimod is currently being investigated in COVID-19 (NCT04280588), with high potential to ameliorate the cytokine storm [329] . It is speculated that sphingosine-1-phosphate agonism results in cytokine suppression via the action of fingolimod in lung endothelial cells [329] . Fingolimod could also stabilize the pulmonary endothelial barrier hence decreasing inflammatory infiltrate and subsequent ARDS [475] . In such case, the delivery of fingolimod loaded NPs to lung endothelial cells following intravenous administration might be warranted.

Another rather critical point to consider is the effect of the excipients. While there is a general notion that organic NPs composed of lipids and biodegradable and/or biocompatible polymers are inert, it has recently become clear that such excipients are not that inert, especially when nanoscopic [476, 477] . For instance, despite being well-established excipients in the pharmaceutical industry and components of several oral formulations, ammonio methacrylate copolymers (types A and B; Eudragit® RL and RS) acquired immunostimulatory properties when formulated into NPs [476] . Within the same context, cationic polyamidoamine dendrimer NPs could induce lung injury via deregulation of the reninangiotensin system which is mainly due to their ability to bind to ACE2 receptors [221] . On the other hand, chitosan NPs showed anti-inflammatory effects on LPS-inflamed Caco-2 cells and significantly inhibited LPS-induced production of TNF-α, IL-8 and MCP-1, among others, in a dose-dependent manner [478] . In such cases care has to be taken so that the excipients used actually provide synergistic rather than opposing actions.

From a formulation perspective, it would be rather interesting to have a nano-system that is capable of loading sufficient drug, preserving its functionality, allocating to the target tissue passively, accumulating in the target cell actively, and even show intracellular trafficking abilities to deliver the drug to a specific compartment and or organelle. This system could even provide a tailored drug release profile, or only release the drug in response to a specific stimulus. In that sense, one would refer to this ridiculously smart system as a nanorobot! But is that all that allure really necessary and possible? While the formulation of such nanorobots would be impressive, would these systems function as expected in-vivo? What would be the cost of these systems and the path required to achieve the necessary approvals? In the current situation, where time is critical and health care systems are struggling to find the means to cover COVID-J o u r n a l P r e -p r o o f 19 related expenses, should not all nano-scientists focus on the simplest, cheapest, most effective solutions? One that would provide the most benefit, in the shortest time possible with lowest costs? We therefore call out for all the nano scientists, to step in and help the potential of nanomedicine in curbing this pandemic materialize. Nanoformulation of drugs represent a promising resource to unify the progress in nanotechnology and understanding of surface chemistry with known drug-delivery mechanisms to enhance the site-specific delivery. With the recurrent spillovers of CoVs in humans, the detection of numerous coronaviruses in bats, including many SARS-related ones, future zoonotic transmission events may continue to occur [8] .The presence of an inhaled carrier system capable of delivering antiviral or immunomodulatory drugs should be available as part of the repertoire in the fight against future outbreaks. 

Is SARS-CoV-2 Also an Enteric Pathogen With Potential Fecal-Oral Transmission? A COVID-19 Virological and Clinical Review

Global shifts in mammalian population trends reveal key predictors of virus spillover risk

The origin and virulence of the 1918 "Spanish" influenza virus

Nanoscale nights of COVID-19. 2020

Pathogenesis of the 1918 pandemic influenza virus

Zika… what next? Vaccine

Prediction and prevention of the next pandemic zoonosis. The Lancet

Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein

Laboratory testing for coronavirus disease 2019 (COVID-19) in suspected human cases: interim guidance

Features, evaluation and treatment coronavirus (COVID-19)

A Review of SARS-CoV-2 and the Ongoing Clinical Trials

Evidence for Gastrointestinal Infection of SARS-CoV-2. Gastroenterology

Covid-19 and the Digestive System

Diagnosing COVID-19: The Disease and Tools for Detection

Presumed asymptomatic carrier transmission of COVID-19

Developing COVID-19 vaccines at pandemic speed

Novel coronavirus treatment with ribavirin: Groundwork for evaluation concerning COVID-19

The Socio-Economic Implications of the Coronavirus and COVID-19 Pandemic: A Review

Estimating the effects of non-pharmaceutical interventions on COVID-19 in Europe

The effect of large-scale anti-contagion policies on the COVID-19 pandemic

Offline: The second wave

Research and development on therapeutic agents and vaccines for COVID-19 and related human coronavirus diseases

Beware of the second wave of COVID-19. The Lancet

The SARS-CoV-2 vaccine pipeline: an overview. Current tropical medicine reports

Discovery of SARS-CoV-2 antiviral drugs through largescale compound repurposing

Biodegradable particulate carrier formulation and tuning for targeted drug delivery

Dexamethasone nanomedicines for COVID-19

Effective treatment of severe COVID-19 patients with tocilizumab

Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The Lancet

Preliminary identification of potential vaccine targets for the COVID-19 coronavirus (SARS-CoV-2) based on SARS-CoV immunological studies

Structure of the RNA-dependent RNA polymerase from COVID-19 virus

Oral and Inhaled Ribavirin Treatment for Respiratory Syncytial Virus Infection in Lung Transplant Recipients

Treatment With Lopinavir/Ritonavir or Interferon-β1b Improves Outcome of MERS-CoV Infection in a Nonhuman Primate Model of Common Marmoset. The Journal of infectious diseases

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Umifenovir treatment is not associated with improved outcomes in patients with coronavirus disease 2019: A retrospective study

Review: Hydroxychloroquine and Chloroquine for Treatment of SARS-CoV-2 (COVID-19). Open Forum Infectious Diseases

Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: A systematic search and a narrative review with a special reference to India and other developing countries. Diabetes & metabolic syndrome

Chloroquine And Hydroxychloroquine Toxicity

StatPearls Publishing: Treasure Island (FL)

Population pharmacokinetics of lopinavir/ritonavir (Kaletra) in HIV-infected patients. Therapeutic drug monitoring

Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers

Extreme bradycardia due to multiple drug-drug interactions in a patient with HIV post-exposure prophylaxis containing lopinavir-ritonavir

Nifedipine-lopinavir/ritonavir severe interaction: a case report

Drug/drug interaction between lopinavir/ritonavir and rosuvastatin in healthy volunteers

Nafamostat mesilate as an anticoagulant during continuous renal replacement therapy in patients with high bleeding risk: a randomized clinical trial

Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Global virus outbreaks: Interferons as 1st responders. in Seminars in immunology

Use of oromucosally administered interferon-alpha in the prevention and treatment of animal diseases

Psychiatric adverse effects of interferon therapy

Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact

Chloroquine inhibits proinflammatory cytokine release into human whole blood

Impact of Hydroxychloroquine/Chloroquine in COVID-19 Therapy: Two Sides of the Coin

Concerns about pharmacokinetic (PK) and pharmacokinetic-pharmacodynamic (PK-PD) studies in the new therapeutic area of COVID-19 infection

Pharmacokinetics of remdesivir and GS-441524 in two critically ill patients who recovered from COVID-19

Comparative therapeutic efficacy of remdesivir and combination lopinavir, ritonavir, and interferon beta against MERS-CoV

Lopinavir/ritonavir (Kaletra).(prescribing information)

Protease inhibitors targeting coronavirus and filovirus entry

These drugs don't target the coronavirus-they target us

Mucoadhesive glycol chitosan nanoparticles for intranasal delivery of hepatitis B vaccine: enhancement of mucosal and systemic immune response. Drug delivery

Nanoparticles that do not adhere to mucus provide uniform and long-lasting drug delivery to airways following inhalation

Diffusion of Macromolecules and Virus-Like Particles in Human Cervical Mucus

Antibody diffusion in human cervical mucus

Influenza A virus surface proteins are organized to help penetrate host mucus. eLife

PEGylation for enhancing nanoparticle diffusion in mucus

Mucus-penetrating nanoparticles for drug and gene delivery to mucosal tissues

Nanomedicine strategies to target coronavirus

Taste Receptors in Upper Airway Innate Immunity

Sensory functions of motile cilia and implication for bronchiectasis

Solitary chemosensory cells in the respiratory and vomeronasal epithelium of the human nose: a pilot study

Extrasensory perception: Odorant and taste receptors beyond the nose and mouth

Motile cilia of human airway epithelia are chemosensory

Role of the bitter taste receptor T2R38 in upper respiratory infection and chronic rhinosinusitis. Current opinion in allergy and clinical immunology

Inhibition of SARScoronavirus infection in vitro by S-nitroso-N-acetylpenicillamine, a nitric oxide donor compound

Personalized nanotherapy by specifically targeting cell organelles to improve vascular hypertension

Particulate matter in cigarette smoke increases ciliary axoneme beating through mechanical stimulation

Inhalable nanoparticulate powders for respiratory delivery

Treatment of fibroses and liver disorders

Nanostructures in drug delivery. Pharmaceutical Nanotechnology: Innovation and Production

Applicability of avidin protein coated mesoporous silica nanoparticles as drug carriers in the lung

SPL creates slow release soluble DEP® remdesivir nanopartic

Summary on compassionate use-Remdesivir Gilead

Modifications to the conventional nanoprecipitation technique: an approach to fabricate narrow sized polymeric nanoparticles. Advanced pharmaceutical bulletin

Hollow silica capsules for amphiphilic transport and sustained delivery of antibiotic and anticancer drugs

Prevention of hepatic stellate cell activation using JQ1-and atorvastatin-loaded chitosan nanoparticles as a promising approach in therapy of liver fibrosis

PubChem Compound Summary for CID 131411

Inhibition of H1N1 influenza virus-induced apoptosis by selenium nanoparticles functionalized with arbidol through ROS-mediated signaling pathways

PubChem Compound Summary for CID 92727, Lopinavir

Modified pullulan nanoparticles for oral delivery of lopinavir: Formulation and pharmacokinetic evaluation

Lopinavir loaded solid lipid nanoparticles (SLN) for intestinal lymphatic targeting

A hybrid design to optimize preparation of lopinavir loaded solid lipid nanoparticles and comparative pharmacokinetic evaluation with marketed lopinavir/ritonavir coformulation

Design, optimization and evaluation of poly-ɛcaprolactone (PCL) based polymeric nanoparticles for oral delivery of lopinavir. Drug development and industrial pharmacy

PubChem Compound Summary for CID 392622, Ritonavir

Encapsulation of ritonavir in solid lipid nanoparticles: in-vitro anti-HIV-1 activity using lentiviral particles

Development of ritonavir solid lipid nanoparticles by Box Behnken design for intestinal lymphatic targeting

Ritonavir loaded surface modified stealth solid lipid nanoparticles: Full factorial design and pharmacokinetic studies

Development of Ritonavir Loaded Nanoparticles: In Vitro and

TAT-conjugated nanoparticles for the CNS delivery of anti-HIV drugs

Development of Innovative Polymer-Based Matricial Nanostructures for Ritonavir Oral Administration

Development of Alginate-Based Nanoparticulate Drug Delivery System for Anti HIV Drug Ritonavir

Compound Summary-Favipiravir

DFT/QTAIM analysis of favipiravir adsorption on pristine and silicon doped C20 fullerenes

PubChem Compound Summary for CID 37542, Ribavirin

Development of biodegradable nanoparticles for liver-specific ribavirin delivery

Darunavir-loaded lipid nanoparticles for targeting to HIV reservoirs

Effect of particle size on oral bioavailability of darunavir-loaded solid lipid nanoparticles

PubChem Compound Summary for CID 3652

Development and Characterization of Hydroxyl Chloroquine Sulphate (HCQ) Nanoparticles

Cholesterol-modified hydroxychloroquine-loaded nanocarriers in bleomycin-induced pulmonary fibrosis

Significantly enhanced tumor cellular and lysosomal hydroxychloroquine delivery by smart liposomes for optimal autophagy inhibition and improved antitumor efficiency with liposomal doxorubicin

PubChem Compound Summary for CID 2719, Chloroquine

Improving encapsulation of hydrophilic chloroquine diphosphate into biodegradable nanoparticles: A promising approach against Herpes virus simplex-1 infection

Chloroquine diphosphate bearing dextran nanoparticles augmented drug delivery and overwhelmed drug resistance in Plasmodium falciparum parasites

In vitro evaluation of chloroquine-loaded and heparin surface-functionalized solid lipid nanoparticles

Design of gelatin nanoparticles as swelling controlled delivery system for chloroquine phosphate

Fabrication and efficacy evaluation of chloroquine nanoparticles in CFA-induced arthritic rats using TNF-α ELISA

The Impact of nanochloroquine on restoration of hepatic and splenic mitochondrial damage against rodent malaria

Formulation of polymeric iron nano-chloroquine phosphate antimalarial drug via polyol method

Synthesis and Characterization of Biogenic Chloroquine Silver Nanoparticles as Potential Anticancer Agent against Neuroblastoma Cells

Optimization of the formulation and in-vitro evaluation of chloroquine loaded chitosan nanoparticles using ionic gelation method

Nano-encapsulation and characterization of baricitinib using poly-lactic-glycolic acid co-polymer

TMPRSS2-Inhibitors Play a role in Cell Entry Mechanism of COVID-19: An Insight into Camostat and Nefamostat

Enhanced stability of oral insulin in targeted peptide ligand trimethyl chitosan nanoparticles against trypsin

Properties of poly(lactic-co-glycolic acid) nanospheres containing protease inhibitors: Camostat mesilate and nafamostat mesilate

Recombinant human ACE2: potential therapeutics of SARS-CoV-2 infection and its complication

PubChem Compound Summary for CID 71306834, Interferon alfa-2B

Development and evaluation of a dry powder formulation of liposome-encapsulated oseltamivir phosphate for inhalation. Drug delivery

TamiGold': phospha-oseltamivir-stabilised gold nanoparticles as the basis for influenza therapeutics and diagnostics targeting the neuraminidase

Functionalized selenium nanoparticles enhance the anti-EV71 activity of oseltamivir in human astrocytoma cell model. Artificial cells, nanomedicine, and biotechnology

Silver nanoparticle based codelivery of oseltamivir to inhibit the activity of the H1N1 influenza virus through ROSmediated signaling pathways

Critical determinants of uptake and translocation of nanoparticles by the human pulmonary alveolar epithelium

Role of particle size in phagocytosis of polymeric microspheres

The Lung Macrophage in SARS-CoV-2 Infection: A Friend or a Foe? Frontiers in Immunology

Alveolar macrophage dysfunction and cytokine storm in the pathogenesis of two severe COVID-19 patients

Monocytes and macrophages, targets of SARS-CoV-2: the clue for Covid-19 immunoparalysis. bioRxiv

Poly (DL-lactide-coglycolide) nanoparticle-based inhalable sustained drug delivery system for experimental tuberculosis

Nebulization of biodegradable nanoparticles: impact of nebulizer technology and nanoparticle characteristics on aerosol features

Spray freeze drying for dry powder inhalation of nanoparticles

Pulmonary delivery of inhalable nanoparticles: dry powder inhalers. Therapeutic delivery

Dry powder inhalers: a focus on advancements in novel drug delivery systems

Preparation and characterization of quercetin-loaded solid lipid microparticles for pulmonary delivery

Beclomethasone-loaded lipidic nanocarriers for pulmonary drug delivery: preparation, characterization and in vitro drug release

Formulation and nebulization of fluticasone propionate-loaded lipid nanocarriers

Development and characterization of PLA nanoparticles for pulmonary drug delivery: Co-encapsulation of theophylline and budesonide, a hydrophilic and lipophilic drug

Feasibility Study of Mesoporous Silica Particles for Pulmonary Drug Delivery: Therapeutic Treatment with Dexamethasone in a Mouse Model of Airway Inflammation

A comparative pulmonary pharmacokinetic study of budesonide using polymeric nanoparticles targeted to the lungs in treatment of asthma

Solubilization of beclomethasone dipropionate in sterically stabilized phospholipid nanomicelles (SSMs): physicochemical and in vitro evaluations. Drug design, development and therapy

Dexamethasone palmitate large porous particles: A controlled release formulation for lung delivery of corticosteroids

Evaluation of a nanoemulsion-based formulation for respiratory delivery of budesonide by nebulizers

Inhalable nanoparticles, a non-invasive approach to treat lung cancer in a mouse model

Formulation and characterization of inhalable magnetic nanocomposite microparticles (MnMs) for targeted pulmonary delivery via spray drying

Formulation, characterization and pulmonary deposition of nebulized celecoxib encapsulated nanostructured lipid carriers

Targeting efficiency and biodistribution of biotinylated-EGF-conjugated gelatin nanoparticles administered via aerosol delivery in nude mice with lung cancer

Arikayce®(amikacin liposome inhalation suspension): US prescribing information

Nebulization of liposome encapsulated antitubercular drugs in guinea pigs

Solid lipid particle-based inhalable sustained drug delivery system against experimental tuberculosis

Lectin-functionalized poly (lactide-co-glycolide) nanoparticles as oral/aerosolized antitubercular drug carriers for treatment of tuberculosis

Cyclosporin A liposome aerosol: Particle size and calculated respiratory deposition

Development of pH-Dependent Nanospheres for Nebulisation-In vitro Diffusion, Aerodynamic and Cytotoxicity Studies

Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Multivalent targeting of AT1 receptors with angiotensin II-functionalized nanoparticles

Angiotensin II mediates angiotensin converting enzyme type 2 internalization and degradation through an angiotensin II type I receptor-dependent mechanism

A hypothesis for pathobiology and treatment of COVID-19: the centrality of ACE1/ACE2 imbalance

Immune response in COVID-19: addressing a pharmacological challenge by targeting pathways triggered by SARS-CoV-2. Signal Transduction and Targeted Therapy

Antihypertensive drugs and risk of COVID-19? The Lancet Respiratory Medicine

Cationic nanoparticles directly bind angiotensin-converting enzyme 2 and induce acute lung injury in mice

IL-6: relevance for immunopathology of SARS-CoV-2

Molecular pathology of emerging coronavirus infections. The Journal of pathology

Lung Surfactant for Pulmonary Barrier Restoration in Patients With COVID-19 Pneumonia

Surface properties in relation to atelectasis and hyaline membrane disease. AMA journal of diseases of children

Surfactant and the adult respiratory distress syndrome. American Review of Respiratory Disease

Exogenous surfactant in acute respiratory distress syndrome: more is better

Surfactant proteins SP-A and SP-D: structure, function and receptors

Surfactant proteins A and D bind CD14 by different mechanisms

Bioinspired pulmonary surfactant-modified nanogels: A promising siRNA delivery system

Identification of a cell membrane protein that binds alveolar surfactant. The American journal of pathology

Mechanism for secretagogue-induced surfactant protein A binding to lung epithelial cells

Receptor-mediated regulation of pulmonary surfactant secretion. Experimental cell research

SP-A-binding protein BP55 is involved in surfactant endocytosis by type II pneumocytes

Role of the PI3-kinase signaling pathway in trafficking of the surfactant protein A receptor P63 (CKAP4) on type II pneumocytes

P63 (CKAP4) as an SP-A receptor: implications for surfactant turnover

Identification and characterization of p63 (CKAP4/ERGIC-63/CLIMP-63), a surfactant protein A binding protein, on type II pneumocytes

HDL is the major source of vitamin E for type II pneumocytes. Free Radical Biology and Medicine

Tailoring of biomimetic high-density lipoprotein nanostructures changes cholesterol binding and efflux

Robust passive and active efflux of cellular cholesterol to a designer functional mimic of high density lipoprotein

Biomimetic, synthetic HDL nanostructures for lymphoma

HDL-mimetic PLGA nanoparticle to target atherosclerosis plaque macrophages

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy. The Lancet Respiratory Medicine

Histopathologic changes and SARS-CoV-2 immunostaining in the lung of a patient with COVID-19

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice

Collagenase loaded chitosan nanoparticles for digestion of the collagenous scar in liver fibrosis: The effect of chitosan intrinsic collagen binding on the success of targeting

Targeting Activated Hepatic Stellate Cells Using Collagen-Binding Chitosan Nanoparticles for siRNA Delivery to Fibrotic Livers

Targeting of drugs and nanoparticles to tumors

Biomimetic amplification of nanoparticle homing to tumors

Peptides selected for binding to clotted plasma accumulate in tumor stroma and wounds

Fibrin specific peptides derived by phage display: characterization of peptides and conjugates for imaging

Inhalation therapy in patients receiving mechanical ventilation: an update

Cellular and molecular pathways of COVID-19 and potential points of therapeutic intervention

Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

Unpuzzling COVID-19: tissue-related signaling pathways associated with SARS-CoV-2 infection and transmission

The pathogenesis and treatment of theCytokine Storm'in COVID-19

How COVID-19 induces cytokine storm with high mortality. Inflammation and Regeneration

Efficacy and safety of sarilumab in patients with active rheumatoid arthritis. Therapeutic advances in musculoskeletal disease

D. van der Heijde, and E.s. investigators, Two years of sarilumab in patients with rheumatoid arthritis and an inadequate response to MTX: safety, efficacy and radiographic outcomes

What is the role of rheumatologists in the era of COVID-19? Autoimmunity reviews

Tocilizumab: A Review in Rheumatoid Arthritis

ACTEMRA® (tocilizumab)-Highlights of prescribing information

Development Briefing Document-PLIVENSIA™ (sirukumab). 2017. 265. FDA US, Sylvant (Siltuximab)-Highlights of prescribing information

LiverTox: clinical and research information on drug-induced liver injury

Safety and pharmacokinetics of olokizumab, an anti-IL-6 monoclonal antibody, administered to healthy male volunteers: A randomized phase I study

Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a randomised Phase IIb study. Annals of the rheumatic diseases

Adalimumab: long-term safety in 23 458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn's disease. Annals of the rheumatic diseases

HUMIRA-Highlights of prescribing information

Adalimumab: a review of side effects

Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study

Safety of extended treatment with anakinra in patients with rheumatoid arthritis. Annals of the rheumatic diseases

ILARIS® (canakinumab)-Highlights of prescribing information

Mavrilimumab: a unique insight and update on the current status in the treatment of rheumatoid arthritis

Efficacy and safety of mavrilimumab in subjects with rheumatoid arthritis

AdisInsight Drugs

Therapeutic blockade of granulocyte macrophage colony-stimulating factor in COVID-19-associated hyperinflammation: challenges and opportunities. The Lancet Respiratory Medicine

AdisInsight Drugs

Emapalumab for the treatment of relapsed/refractory hemophagocytic lymphohistiocytosis

GAMIFANTTM (emapalumab-lzsg)-Highlights of prescribing information

Clinical significance of chemokine receptor antagonists

Anti-HIV-1 activity of weekly or biweekly treatment with subcutaneous PRO 140, a CCR5 monoclonal antibody

Ravulizumab (ALXN1210) in patients with paroxysmal nocturnal hemoglobinuria: results of 2 phase 1b/2 studies

Ravulizumab (ALXN1210) vs eculizumab in C5-inhibitor-experienced adult patients with PNH: the 302 study

Eculizumab: a review of its use in atypical haemolytic uraemic syndrome

SOLIRIS-Highlights of prescribing information

When to Stop Eculizumab in Complement-Mediated Thrombotic Microangiopathies

Complement Inhibition in Coronavirus Disease (COVID)-19: A Neglected Therapeutic Option

AdisInsight Drugs

Siglec-G represses DAMPmediated effects on T cells. JCI insight

Approaching coronavirus disease 2019: Mechanisms of action of repurposed drugs with potential activity against SARS-CoV-2

Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-κB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death

Safety and efficacy of selinexor in relapsed or refractory multiple myeloma and Waldenstrom macroglobulinemia

Tofacitinib: A Review in Rheumatoid Arthritis

XELJANZ / XELJANZ XR (tofacitinib) Adverse Reactions

Ruxolitinib: a potent and selective Janus kinase 1 and 2 inhibitor in patients with myelofibrosis. An update for clinicians. Therapeutic advances in hematology

Serious adverse events during ruxolitinib treatment discontinuation in patients with myelofibrosis

JAKAFI™ (ruxolitinib) -Highlights of prescribing information

Beyond Ruxolitinib: Fedratinib and Other Emergent Treatment Options for Myelofibrosis. Cancer management and research

Fedratinib in myelofibrosis. Blood Advances

Repurposing Immunomodulatory Therapies against Coronavirus Disease 2019 (COVID-19) in the Era of Cardiac Vigilance: A Systematic Review

Duvelisib: a phosphoinositide-3 kinase δ/γ inhibitor for chronic lymphocytic leukemia. Expert opinion on investigational drugs

Repurposing anticancer drugs for COVID-19-induced inflammation, immune dysfunction, and coagulopathy

Duvelisib, a novel oral dual inhibitor of PI3K-δ,γ, is clinically active in advanced hematologic malignancies

COPIKTRA (duvelisib)-Highlights of prescribing infromation

PI3Kδ Inhibition as a Potential Therapeutic Target in COVID-19

A comprehensive review of immunosuppression used for liver transplantation

Apremilast in Psoriasis and Beyond: Big Hopes on a Small Molecule. Indian dermatology online journal

OTEZLA® (apremilast)-Highlights of prescribing infromation

Real-world data on the efficacy and safety of apremilast in patients with moderate-to-severe plaque psoriasis

Cyclosporine: an old weapon in the fight against Coronaviruses

Clinically significant drug interactions with cyclosporin an update

Cyclosporine: a review

Colchicine as a potent anti-inflammatory treatment in COVID-19: can we teach an old dog new tricks?

The NLRP3 inflammasome and the emerging role of colchicine to inhibit atherosclerosis-associated inflammation

Colchicine: a potential therapeutic tool against COVID-19. Experience of 5 patients

Mechanism of action of colchicine in the treatment of gout

Acalabrutinib (ACP-196): a selective second-generation BTK inhibitor

Inhibition of Bruton tyrosine kinase in patients with severe COVID-19

A rationale for blocking thromboinflammation in COVID-19 with Btk inhibitors

Mato Acalabrutinib and Its Therapeutic Potential in the Treatment of Chronic Lymphocytic Leukemia: A Short Review on Emerging Data. Cancer management and research

Fingolimod for multiple sclerosis and emerging indications: appropriate patient selection, safety precautions, and special considerations

A new shield for a cytokine storm

Mechanisms of fingolimod's efficacy and adverse effects in multiple sclerosis

Clinical Pharmacology of Corticosteroids

Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats

Dexamethasone sodium phosphate injection

Systemic glucocorticoid therapy and adrenal insufficiency in adults: A systematic review. Seminars in arthritis and rheumatism

Omnaris, (ciclesonide)

budesonide inhalation suspension) 0.25 mg and 0.5 mg

Focus shifts to antibody cocktails for COVID-19 cytokine storm

Inhibition of NF-κB-mediated inflammation in severe acute respiratory syndrome coronavirus-infected mice increases survival

Exacerbated innate host response to SARS-CoV in aged non-human primates

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet

Diagnostic utility of clinical laboratory data determinations for patients with the severe COVID-19

Correlation Analysis Between Disease Severity and Inflammation-related Parameters in Patients with COVID-19 Pneumonia. MedRxiv

Clinical and biochemical indexes from 2019-nCoV infected patients linked to viral loads and lung injury

IL-1β is a key cytokine that induces trypsin upregulation in the influenza virus-cytokine-trypsin cycle. Archives of virology

Single-cell landscape of bronchoalveolar immune cells in patients with COVID-19

The landscape of lung bronchoalveolar immune cells in COVID-19 revealed by single-cell RNA sequencing

Lung epithelial GM-CSF improves host defense function and epithelial repair in influenza virus pneumonia-a new therapeutic strategy? Molecular and cellular pediatrics

GM-CSF-dependent inflammatory pathways

COVID-19: consider cytokine storm syndromes and immunosuppression

COVID-19, vascular endothelial growth factor (VEGF) and iodide

Complement activation contributes to severe acute respiratory syndrome coronavirus pathogenesis

The role of C5a in acute lung injury induced by highly pathogenic viral infections. Emerging microbes & infections

Blockade of the C5a-C5aR axis alleviates lung damage in hDPP4-transgenic mice infected with MERS-CoV. Emerging microbes & infections

Highly pathogenic coronavirus N protein aggravates lung injury by MASP-2-mediated complement overactivation

Interleukin-6 use in COVID-19 pneumonia related macrophage activation syndrome

B and T cells collaborate in antiviral responses via IL-6, IL-21, and transcriptional activator and coactivator, Oct2 and OBF-1. The Journal of experimental medicine

COVID-19 poses a riddle for the immune system

62 -Interleukin-6 inhibition

The hematopoietic factor GM-CSF (granulocyte-macrophage colony-stimulating factor) promotes neuronal differentiation of adult neural stem cells in vitro

Elevated interleukin-6 and severe COVID-19: A meta-analysis

The Role of Cytokines including Interleukin-6 in COVID-19 induced Pneumonia and Macrophage Activation Syndrome-Like Disease

Urgent Appeal from International Society for Aerosols in Medicine (ISAM) During COVID-19: Clinical Decision Makers and Governmental Agencies Should Consider the Inhaled Route of Administration: A Statement from the ISAM Regulatory and Standardization Issues Networking Group

Theravance Biopharma announces first patient dosed in phase 2 study of TD-0903 for the treatment of hospitalized patients with acute lung injury caused by COVID-19

Bevacizumab loaded solid lipid nanoparticles prepared by the coacervation technique: preliminary in vitro studies

A new paradigm for antiangiogenic therapy through controlled release of bevacizumab from PLGA nanoparticles. Scientific reports

In vivo efficacy of bevacizumab-loaded albumin nanoparticles in the treatment of colorectal cancer

Chitosan-coated PLGA nanoparticles of bevacizumab as novel drug delivery to target retina: optimization, characterization, and in vitro toxicity evaluation

Transscleral delivery of bevacizumab-loaded chitosan nanoparticles

The effect of nanoparticle conjugated with bevacizumab in liver cancer

Ocular implant containing bevacizumab-loaded chitosan nanoparticles intended for choroidal neovascularization treatment

Hyaluronategold nanoparticle/tocilizumab complex for the treatment of rheumatoid arthritis

Interleukin-6 neutralization by antibodies immobilized at the surface of polymeric nanoparticles as a therapeutic strategy for arthritic diseases

Administration of IL-1Ra Chitosan Nanoparticles Enhances the Therapeutic Efficacy of Mesenchymal Stem Cell Transplantation in Acute Liver Failure

Synthesis of selfassembled IL-1Ra-presenting nanoparticles for the treatment of osteoarthritis

How Antibody Surface Coverage on Nanoparticles Determines the Activity and Kinetics of Antigen Capturing for Biosensing

Substrate-permeable encapsulation of enzymes maintains effective activity, stabilizes against denaturation, and protects against proteolytic degradation

PEGylated PLGA nanoparticles as protein carriers: synthesis, preparation and biodistribution in rats

The effect of a water/organic solvent interface on the structural stability of lysozyme

Protein instability in poly (lactic-co-glycolic acid) microparticles. Pharmaceutical research

The protective effect of albumin on bevacizumab activity and stability in PLGA nanoparticles intended for retinal and choroidal neovascularization treatments

Why does PEG 400 co-encapsulation improve NGF stability and release from PLGA biodegradable microspheres? Pharmaceutical research

Stabilization of proteins encapsulated in injectable poly (lactide-co-glycolide)

Nuclear delivery of recombinant OCT4 by chitosan nanoparticles for transgene-free generation of protein-induced pluripotent stem cells

Nuclear and cytoplasmic delivery of lactoferrin in glioma using chitosan nanoparticles: Cellular location dependent-action of lactoferrin

Thermo scientific pierce crosslinking technical handbook

Synthesis of biomolecule-modified mesoporous silica nanoparticles for targeted hydrophobic drug delivery to cancer cells

Noncovalent Surface Locking of Mesoporous Silica Nanoparticles for Exceptionally High Hydrophobic Drug Loading and Enhanced Colloidal Stability

Fedratinib-Application number: 212327Orig1a000

PubChem Compound Summary for CID 71226662, Acalabrutinib

Immunomodulation in COVID-19. The Lancet Respiratory Medicine

Complement as a target in COVID-19?

Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease

Inhaled corticosteroids in virus pandemics: a treatment for COVID-19? The Lancet Respiratory Medicine

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Asthma, COPD and bronchitis are just components of airway disease

Weathering the Cytokine Storm in Susceptible Patients with Severe SARS-CoV-2 Infection. The journal of allergy and clinical immunology

Amikacin Liposome Inhalation Suspension (ALIS) Penetrates Non-tuberculous Mycobacterial Biofilms and Enhances Amikacin Uptake Into Macrophages

The inhaled corticosteroid ciclesonide blocks coronavirus RNA replication by targeting viral NSP15

Chitosan/hyaluronic acid/plasmid-DNA nanoparticles encoding interleukin-1 receptor antagonist attenuate inflammation in synoviocytes induced by interleukin-1 beta

Efficient VEGF targeting delivery of DOX using Bevacizumab conjugated SiO2@ LDH for antineuroblastoma therapy

Recombinant Human CD24 Fc Chimera-Catalog Number

The GReek study in the Effects of Colchicine in COvid-19 complications prevention (GRECCO-19 study): rationale and study design

Targeted nano-drug delivery of colchicine against colon cancer cells by means of mesoporous silica nanoparticles

Polymeric nanoparticles as potential carriers for topical delivery of colchicine: development and in vitro characterization

Development and Characterization Colchicine-Loaded PEGylated Gelatin Nanoparticles for Targeted Delivery to Tumor

Appraisal of antigout potential of colchicine-loaded chitosan nanoparticle gel in uric acid-induced gout animal model

Fabrication and in-vivo evaluation of lipid nanocarriers based transdermal patch of colchicine

Lipid Nanoparticle-Mediated Delivery of Enhanced Costimulation Blockade to Prevent Type 1 Diabetes

Tofacitinib-Loaded Solid Lipid Nanoparticles Inhibits Dendritic Cell Antigen Presenting Functions and Achieve Selective In Vivo Targeting

Fabrication, characterization and in vitro release kinetics of tofacitinib-encapsulated polymeric nanoparticles: a promising implication in the treatment of rheumatoid arthritis

Ruxolitinib-conjugated gold nanoparticles for topical administration: An alternative for treating alopecia? Medical Hypotheses

Product Quality Review-Application number 212327Orig1s000

Liposomal dexamethasone inhibits tumor growth in an advanced human-mouse hybrid model of multiple myeloma

Dexamethasone-loaded block copolymer nanoparticles induce leukemia cell death and enhance therapeutic efficacy: a novel application in pediatric nanomedicine

Dexamethasone loaded PLGA nanoparticles for potential local treatment of oral precancerous lesions. Pharmaceutical Development and Technology

Development of Dexamethasone Loaded Nanoparticles Utilizing Various Combination of Triblock Polymer for the Treatment of Retinal Diseases

Mucoadhesive dexamethasone-glycol chitosan nanoparticles for ophthalmic drug delivery

Development of chitosan nanoparticles coated with hyaluronic acid for topical ocular delivery of dexamethasone

Developing Biodegradable Nanoparticles Loaded with Mometasone Furoate for Potential Nasal Drug Delivery

Topical nanostructured lipid carrier based hydrogel of mometasone furoate for the treatment of psoriasis

Development and evaluation of solid lipid nanoparticles of mometasone furoate for topical delivery

Nanoencapsulation in lipid-core nanocapsules controls mometasone furoate skin permeability rate and its penetration to the deeper skin layers

Solu-Cortef® (hydrocortisone sodium succinate for injection, USP)

Minimization of local and systemic adverse effects of topical glucocorticoids by nanoencapsulation: in vivo safety of hydrocortisone-hydroxytyrosol loaded chitosan nanoparticles

Hydrocortisone-loaded poly (ε-caprolactone) nanoparticles for atopic dermatitis treatment. Pharmaceutical development and technology

Liposomeencapsulated prednisolone phosphate inhibits growth of established tumors in mice

SOLU-MEDROL (methylprednisolone sodium succinate for injection, USP)

Clares-Naveros, Nano-engineering of biomedical prednisolone liposomes: evaluation of the cytotoxic effect on human colon carcinoma cell lines

Preparation and in vitro/pharmacokinetic/pharmacodynamic evaluation of a slow-release nano-liposomal form of prednisolone. Drug delivery

Liposomal steroid nano-drug is superior to steroids as-is in mdx mouse model of Duchenne muscular dystrophy

Liposomal prednisolone inhibits vascular inflammation and enhances venous outward remodeling in a murine arteriovenous fistula model

Nano-drugs based on nano sterically stabilized liposomes for the treatment of inflammatory neurodegenerative diseases

Prednisolone-containing liposomes accumulate in human atherosclerotic macrophages upon intravenous administration

Prednisoloneloaded nanocapsules as ocular drug delivery system: development, in vitro drug release and eye toxicity

Formulation and Optimization of Nanoparticale by 32 Factorial Design for Colon Targeting

Subconjunctival nano-and microparticles sustain retinal delivery of budesonide, a corticosteroid capable of inhibiting VEGF expression. Investigative ophthalmology & visual science

Screening of budesonide nanoformulations for treatment of inflammatory bowel disease in an inflamed 3D cell-culture model. ALTEX-Alternatives to animal experimentation

Budesonide-Loaded Eudragit S 100 Nanocapsules for the Treatment of Acetic Acid-Induced Colitis in Animal Model

Budesonide loaded PLGA nanoparticles for targeting the inflamed intestinal mucosa-Pharmaceutical characterization and fluorescence imaging

Effect of Poly (vinyl alcohol) on Nanoencapsulation of Budesonide in Chitosan Nanoparticles via Ionic Gelation and Its Improved Bioavailability

A comprehensive review of immunosuppression used for liver transplantation

Rapamycin loaded solid lipid nanoparticles as a new tool to deliver mTOR inhibitors: formulation and in vitro characterization

Biodegradable sirolimus-loaded poly (lactide) nanoparticles as drug delivery system for the prevention of in-stent restenosis in coronary stent application

Nanoparticles effectively target rapamycin delivery to sites of experimental aortic aneurysm in rats

Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin

Effective attenuation of vascular restenosis following local delivery of chitosan decorated sirolimus liposomes. Carbohydrate polymers

Preformulation studies of a liposomal formulation containing sirolimus for the treatment of dry eye disease

Periadventitial application of rapamycin-loaded nanoparticles produces sustained inhibition of vascular restenosis

Sirolimus formulation

Preparation of sustained release apremilast-loaded PLGA nanoparticles: in vitro characterization and in vivo pharmacokinetic study in rats

Formulation, optimization and in vitro evaluation of nanostructured lipid carriers for topical delivery of apremilast

Nanoparticulate fingolimod delivery system based on biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate)(PHBV): design, optimization, characterization and invitro evaluation. Pharmaceutical development and technology

A novel liposomal formulation of FTY720 (fingolimod) for promising enhanced targeted delivery

Oral cyclosporine A-the current picture of its liposomal and other delivery systems. Cellular & molecular biology letters

Lipid nanoparticles for cyclosporine A administration: development, characterization, and in vitro evaluation of their immunosuppression activity

Nanoparticle-mediated targeting of cyclosporine A enhances cardioprotection against ischemia-reperfusion injury through inhibition of mitochondrial permeability transition pore opening

Cyclosporin A loaded PLGA nanoparticle: preparation, optimization, in-vitro characterization and stability studies

Immunosuppressive activity of size-controlled PEG-PLGA nanoparticles containing encapsulated cyclosporine A

A highly potent lymphatic system-targeting nanoparticle cyclosporine prevents glomerulonephritis in mouse model of lupus

Improved dermal delivery of cyclosporine a loaded in solid lipid nanoparticles

Cyclosporin A-loaded poly (d, llactide) nanoparticles: a promising tool for treating alopecia

A novel chitosan nanocapsule for enhanced skin penetration of cyclosporin A and effective hair growth in vivo

Bioavailability and pharmacokinetics of cyclosporine A-loaded pH-sensitive nanoparticles for oral administration

Preparation and in vitro and in vivo characterization of cyclosporin A-loaded, PEGylated chitosan-modified, lipid-based nanoparticles

Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer

Development of mucoadhesive nanoparticulate system of ebastine for nasal drug delivery

Nanoparticulate ebastine formulations

Endothelial cells are central orchestrators of cytokine amplification during influenza virus infection

Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics

Chitosan nanoparticles: a positive modulator of innate immune responses in plants

Chitosan nanoparticles reduce LPS-induced inflammatory reaction via inhibition of NF-κB pathway in Caco-2 cells

SM is thankful to the University of Cologne for funding provided in the framework of Excellence Support Program to establish a UoC-Forum in the field of Nanoparticle-based RNA-Carriers. Graphical abstract, Figures 1, 3 and 4 were created by Biorender.com