BioNtech and Pfizer are a huge achievement for molecular medicine and biotechnology. They also represent a big milestone for nanomedicine, which has struggled to gain mainstream recognition so far due to translation challenges. They are a success for all those scientists who have worked to optimize nanoformulations for the efficient packaging and safe delivery of genetic material. They epitomize some of the ideas behind the concept of drug delivery, and the founding principles of nanomedicine — that biocompatible rationally engineered materials, thanks to their nano-size and physicochemical characteristics, can protect drug cargos from degradation and offer control over their biodistribution and intracellular localization and release.
With respect to other approaches, mRNA-based therapies have several advantages. mRNA delivery is safer than whole virus or DNA delivery as mRNA is not infectious and cannot be integrated into the host genome; while DNA needs to reach the nucleus to be decoded, mRNA is processed directly in the cytosol; mRNA has a short half-life, which can be regulated by molecular design; finally, it is immunogenic, which might represent an advantage for vaccine design, yet its immunogenicity can be modulated with molecular engineering techniques5. However, to be safely and efficiently transported in vivo without being degraded in the circulation, and to reach the cytosol across the cellular plasma membrane, mRNA needs a carrier.
For many mRNA-based therapeutics, including BNT162b2 and mRNA-1273, the vehicles of choice are lipid nanoparticles (although other materials have also been used)5. Complexed with positively-charged lipids, mRNA is more stable and resistant to RNase-mediated degradation and forms self-assembled virus-sized particles that can be administered via different routes6. Once endocytosed, the lipid nanoparticles promote endosomal escape, and release their genetic cargo in the cytosol, where the mRNA is translated into antigenic proteins, kick-starting the immune system machinery into producing neutralizing antibodies. Both BNT162b2 and mRNA-1273 deliver mRNA encoding genetic variants of the SARS-CoV-2 spike protein that are more stable and immunogenic than the natural protein. A current drawback of these formulations is that their long-term storage requires low temperatures, posing logistical hurdles to their potential distribution and administration, in particular for regions of the global south.
Date: 4 Aug
