key: cord-0011962-xb8y371p authors: Mehta, Meenu; Chellappan, Dinesh K; Wich, Peter R; Hansbro, Nicole G; Hansbro, Philip M; Dua, Kamal title: miRNA nanotherapeutics: potential and challenges in respiratory disorders date: 2020-04-09 journal: nan DOI: 10.4155/fmc-2020-0066 sha: f93313582f9db3c3fcfbb1ff00564560f92e41ad doc_id: 11962 cord_uid: xb8y371p nan formerly assumed. They not only bind to complementary sequences but also to similar sequences that lead to show unwanted phenotypes, adverse side effects and sometimes completely negating the therapeutic effect of miRNA. Cell membrane barriers: the naked miRNAs are not free to disperse across the cell membrane. This is because of their comparatively larger molecular weight and polyanionic nature [8] . MiRNA inhibitors & nanotechnology: a symbiotic association miRNA inhibitors/antagomirs (AMO) are synthetic miRNA antagonists, also known as miRNA silent agents. They are commonly found bound to the miRNA. They mask the target site, which essentially avoids interaction with the miRNA, enabling them to be translated. This approach has the benefit of annulling the likely off-target effects of a wide range of miRNAs [9] . Like AMO, miRNAs are not degraded by this method. Thus, specific functions of the miRNAs remain intact in other genes. Several reported studies have shown a greater potential for AMO such as AMO-106a and AMO-9, in asthma and hyper-reactive steroidal airways in respiratory diseases [10] . Nanotechnology has made significant strides in recent years, in both developing new materials and also with their applications. These advancements have led to the development of new DNA and RNA delivery systems to monitor diseases that can be used, instead of viral vectors [11] . Inorganic varieties namely, gold, silver, calcium phosphate, graphene, quantum dots, iron oxide and silica; organic substances namely, chacosanes, fabric, protein/peptides and aptamers; polymerized nanomaterials may be used in the architectural creation of these non-viral vectors. Nanomaterial-based delivery systems have several advantages over viral vector delivery systems, which may include, having less immune response and design versatility to work in low cytotoxicity areas [12] . For example, proteins, antibodies and carbohydrates could be used for combining nanoparticles in carboxy and amino groups. The cellular absorption of miRNA is increased because of its small size and the probability of mixing cell penetration peptides [13] . Despite these potential benefits, the applications of nanobiotechnology in the respiratory area are still in its infancy and have not yet made its mark in comparison to other disorders. Few attempts which are made in the respiratory area have been discussed below. One of the recent attempts made was to deliver miR146a using polymeric nanoparticles for the treatment of chronic obstructive pulmonary disease. Results showed that miR-146a has maintained its gene and protein functional structure. The high concentration of miR-146a-nanoparticles decreased the IRAK1 target gene expression to 40% [14] . In addition to that, there is another study which had reported that the presence of miR-660 lipidnanoparticles decreased lung cancer tumor growth by inducing P53-dependent cell cycle arrest in low doses when compared with the controls [15] . McKiernan et al. prepared nanoparticles of miR-126 with cationic polymers and demonstrated their ability to promote the incorporation of miRNA into the CFBE41o cells (the human F508del transmembrane epithelial bronchial regulator for cystic fibrosis), thus significantly decreasing the expression of TOM1 [16] . Neutral lipid delivery systems have been developed to minimize the adverse impacts and nonspecific interactions of cationic particles. In a non-small-cell lung cancer mouse model for efficacy, a neutral fat emulsion was compared and correlated with synthetic miRNA-34a and let-7 [17] . When compared with cationic lipoplexes, the systemic administration of the neutral lipid particles demonstrated lesser hepatic aggregation, and more uniformly distributed pattern in other tissues such as the lungs. Treatment with the miRNA imitation caused a decrease in the tumor size and an increase in the tissue level of miR-34a [18] . Shi et al. developed a codelivery system that comprised of solid lipid nanoparticles enclosing miRNA-34a and paclitaxel (PTX) for synergistic effect to target lung cancer cells. The drugs administered co-operatively and more effectively blocked the metastatic production of BF10-CD44 + originating in the lung. In addition, this approach also decreased the doses of PTX, thereby, reducing the side effects associated with PTX alone [19] . A similar study was conducted by Song et al. in 2020, which also encapsulated myricetin and siRNA in mesoporous silica nanoparticles and showed its synergistic effect to suppress tumor growth in lung cancer cells with lesser side effects [20] . The expanded and in-depth research in understanding the roles of miRNA opens up new possibilities for pulmonary disorders. The blend of miRNA with nanotechnology paves the way to achieve enhanced cellular uptake, endosomal escape and improved bioavailability. However, there are several challenges related with the unknown structure and stoichiometry of polymers along with the accumulation of nanoparticles in normal organs. Other key issues awaiting The global burden of pulmonary diseases: most prevalent problems and opportunities for improvement Targeting microRNAs using nanotechnology in pulmonary diseases Identification of biomarkers and genetic approaches toward chronic obstructive pulmonary disease Targeting microRNA function in respiratory diseases: mini-review RNAi nanomedicines: challenges and opportunities within the immune system Sequence-dependent stimulation of the mammalian innate immune response by synthetic siRNA Therapeutic prospects of microRNAs in cancer treatment through nanotechnology MicroRNAs as therapeutics for future drug delivery systems in treatment of lung diseases Nanoparticle-antagomiR based targeting of miR-31 to induce osterix and osteocalcin expression in mesenchymal stem cells Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model Multi-drug resistant Mycobacterium tuberculosis & oxidative stress complexity: emerging need for novel drug delivery approaches Recent advances in nanomaterials for gene delivery -a review Surface modification of microspheres with steric stabilizing and cationic polymers for gene delivery Polymeric nanoparticles for the delivery of miRNA to treat chronic obstructive pulmonary disease (COPD) Coated cationic lipid-nanoparticles entrapping miR-660 inhibit tumor growth in patient-derived xenografts lung cancer models Targeting miRNA-based medicines to cystic fibrosis airway epithelial cells using nanotechnology A combinatorial microRNA therapeutics approach to suppressing non-small-cell lung cancer Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice Dual drugs (microRNA-34a and paclitaxel)-loaded functional solid lipid nanoparticles for synergistic cancer cell suppression Folic acid (FA)-conjugated mesoporous silica nanoparticles combined with MRP-1 siRNA improves the suppressive effects of myricetin on non-small-cell lung cancer (NSCLC)