A nice statement of the complexity of the task that went into saving our lives.

[NNadir]

I don't know about you, but I know that my life was saved by RNA vaccines, in my case, the Moderna vaccines.

For my whole career I was skeptical of nucleic acid therapy, because of the complexity of the task. Happily, I was proved wrong.

Besides Kariko's brilliant discovery of the possibility of substituting pseudouridine for uridine in RNA - it seems obvious now, but trust me it wasn't and she deserves the Nobel Prize eventually - there was the matter of delivering hydrophilic nucleic acids by getting to pass intact through hydrophobic cell and organelle membranes.

This was not something that just "popped out" of nowhere. This was decades and decades of work, hard work, that came to fruition at just the right time.

Anyway, I came across this nice statement of the combinatorial challenge of making this work based on research into further refinements of the challenge met but still subject to improvement:

Hierarchical Self-Assembly Route to “Polyplex-in-Hydrophobic-Core” Micelles for Gene Delivery, Sundiata Kly, Lucas J. Andrew, Erin G. Moloney, Yuhang Huang, Jeremy E. Wulff, and Matthew G. Moffitt Chemistry of Materials 2021 33 (17), 6860-6875

The statement of the challenge that I found therein:

Gene therapy opens up new routes for the treatment of chronic disease by modulating gene expression in targeted cells through the delivery of nucleic acids. (1) Although viral delivery vectors can lead to high transfection efficiencies in animal models, their clinical applications are limited by potential immunogenicity and mutagenesis. (2,3) In addition, the limited size capacity of viral particles precludes the delivery of larger nucleic acids required for some gene therapies. (4) Therefore, the development of safe and effective nonviral gene delivery vectors has become an intense field of investigation at the interface of materials science and molecular biology. (2,3,5?11) In particular, polymer nanoparticles (or PNPs) offer a number of advantages for gene delivery compared to their lipid-based counterparts, including stability, ease of functionalization, and variability of properties. (12?16)

To serve as effective gene delivery vehicles, PNP vectors should be designed with four main characteristics. First, they should provide stable encapsulation of nucleic acids while protecting them from constituents in the extracellular environment; for example, both deoxyribonucleases (DNases) and ribonucleases (RNases) will bind and degrade exposed exogenic nucleic acids in the blood. (4,17,18) Second, PNP vectors should disperse in the bloodstream and deliver nucleic acids to target cells through passive or active targeting. (4,17,18) Third, they should facilitate cellular uptake followed by the release of nucleic acids to trigger the desired transfection events. (4,17,18) Finally, the vector material should be broken down and excreted by the patient with minimal toxicological effects. (4,17,18)

Meeting those 4 conditions in a combinatorially effective way was a huge, huge, huge triumph, unbelievable really.

As I understand it, the technology behind the Moderna and the BNT/Pfizer vaccines was not polymer based but relied on quasi-liposomic ionizable lipids incorporated into standard liposome lipids that nonetheless can be said to have engaged in self assembly, self assembly being the difficult key that underlies all life on Earth and perhaps elsewhere.

Many of us, myself included I'm sure, owe our lives to this science.

[4dog]

1. Based on the labor of many thousands of mostly forgotten chemists

patiently elucidating the structures of so many organic compounds and how they relate to life.

[NNadir]

2. Absolutely true. I certainly have a sense of that. n/t.