key: cord-320501-xqgqq55q
authors: Theobald, Nigel
title: Emerging vaccine delivery systems for COVID-19: Functionalised silica nanoparticles offer a potentially safe and effective alternative delivery system for DNA/RNA vaccines and may be useful in the hunt for a COVID-19 vaccine
date: 2020-06-24
journal: Drug Discov Today
DOI: 10.1016/j.drudis.2020.06.020
sha: 
doc_id: 320501
cord_uid: xqgqq55q

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from the disease the social, healthcare and economic consequences are likely to persist for years. While drug treatments may emerge, which reduce the impact of the disease, vaccination represents the most appropriate means to bring the virus under control in developed and developing countries equally. Multiple technologies are being deployed to identify a safe and effective vaccine.

In the case of COVID-19 most vaccines in early development are targeting the so-called spike protein. This protein is expressed on the surface of the virus and allows the virus to bind to the ACE2 receptor on the cell surface, initiating fusion with and uptake by the cell, followed by the chain of events leading to virus replication.

A vaccine typically contains an antigen made from weakened or killed forms of the microbe/virus, its toxins, or one of its surface proteins. The antigen stimulates the body's immune system to recognise the agent as a threat, and destroy the associated virus. The antigen protein(s) can be administered directly, usually together with an adjuvant to enhance the immune response. In the case of COVID-19, the spike protein or epitopes, including the receptor binding domain, are used as the antigen.

However, rather than administer the protein antigen, alternative techniques have been developed to administer the DNA or RNA which encodes the antigenic protein. A DNA/RNA vaccine introduces the DNA/RNA into the cell to produce the spike protein, which will then be internally processed by the cell and presented on the cell surface to immune cells. This way, the virus or its antigen is presented in a similar manner to during infection with the wildtype virus and thus will trigger a more natural immune response. By doing so, the immune system should activate both killer T cells but also neutralise antibodies to combat the virus.

The biggest challenge facing DNA/RNA vaccines is ensuring the host cell accepts the introduced genetic material. There are two common methods of introducing the DNA/RNA into J o u r n a l P r e -p r o o f (creatine phosphokinase) levels in the blood of six participants. The researchers acknowledged that "The electroporation procedure has been shown to carry some potential of transient muscle damage in animal models, evident as increased numbers of fibres with central nucleoli and damaged myofibrillar bundles." 3 In addition, the equipment required together with the training of medical staff in its use will preclude widespread adoption of electroporation as a mass vaccination methodology.

Liposomal encapsulation of drugs with bioavailability issues was a proven approach in small molecule pharma, and it was apparent to biopharma R&D scientists that LNPs could meet the basic requirements of an RNA/DNA delivery system too, namely to protect nucleic acid from in vivo digestion as it travels to the target. Additionally, LNPs can be produced with catatonic outer membranes to allow cell entry.

However, solid LNPs 4 have some significant disadvantages to be overcome, including cell toxicity; stimulating the release of systemic inflammatory cytokines; possible accumulation in the liver and spleen, with the resulting possibility of hepato-toxicity; low drug payload for hydrophilic molecules; and the potential of the reticuloendothelial system (RES) as a major route of clearance if liposomes are administered systemically. The challenge is delivering enough nucleic acid into the cells without unwanted side effects. This level of variation in performance has led scientists to consider alternatives to LNPs.

Widely used in many different pharmaceutical and food situations, silica and has been proven to be safe in these various uses. As scientists looked to alternative carriers that could be adapted to encapsulate and protect nucleic acids, mesoporous silica nanoparticles (MSNs)silica-based nanostructured materials with excellent biocompatibility and chemical stability - This surface simply and effectively traps and protects nucleic acids (such as mRNA/pDNA) from nuclease enzymes as it travels to the cells. Once inside the cell, the DNA/RNA is released and will result in synthesis of the foreign/target protein which will activate the immune system, leading to both a cellular and humoral immune response. The cellular response (T cells) can sense and kill infected cells and the humoral response (antibodies) will bind to the virus and (1) neutralise its capability to bind to the target cell and (2) be increasingly cleared by phagocytic mechanisms. The new delivery system is called Nuvec ® . Figure 1 shows the end-to-end mode of action for Nuvec ® as it delivers DNA/RNA to antigen presenting cells: the Nuvec ® particle carrying the DNA/RNA attaches to the cell membrane, by charge attraction, and is taken up into the cell via general and dynamin endocytosis. Once inside the endosome, the association of DNA with Nuvec changes as a consequence of the acidic environment of the endosome, releasing some DNA/RNA.

A crucial feature of Nuvec ® is that, compared to lipid-based delivery systems, it does not disrupt the cell membrane as it enters the cell and does not exhibit inflammatory response at the site of injection or any unwanted systemic side-effects. A series of studies have supported the safety, efficacy and mode of action of Nuvec ® and the particle is being used in late stage pre-clinical studies.

In addition, Nuvec ® 's capability to bind more than one plasmid has the potential to assist viral vector delivery. This ensures that in a multi-plasmid transfection approach, each cell will be exposed to all plasmids at the same time and can lead to less plasmid necessary to achieve J o u r n a l P r e -p r o o f the same transfection efficacy. Also during in vivo delivery of the vaccine, Nuvec ® and the viral vector can work synergistically to deliver the payload. Nuvec ® 's particle will be sensed and picked up by macrophages and antigen-presenting cells.

The presence of PEI will facilitate the endosomal disruption and release of nucleic acid but also presents a danger signal that will up regulate surface markers and hence attract immune cells and boost the immune response.

The global urgency of the COVID-19 pandemic has brought more than 25 years of research into nucleic acid-based vaccines and therapeutics into the limelight. The pharmaceutical industry, government agencies and WHO are working hard to find a COVID-19 vaccine. As researchers search for their ideal delivery platforms, safe and effective alternatives to established technologiesincluding emerging technologies like such as Nuvec ®can be considered.

COVID-19 Dashboard by the Center for Systems Science and Engineering

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Efficient and regulated erythropoietin production by naked DNA injection and muscle electroporation

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