[entee]

One thing to note is that mRNA therapeutics are a really tough area in part because:

1.) RNA and the lipids used to get it inside a cell are inherently pretty immunogenic (a huge plus for a vaccine). If you think about it, you basically never see free mRNA/DNA in the blood stream other than if something has gone wrong (usually a virus), so the immunogenicity here is pretty ancient.

2.) RNA gets shunted to the liver and chopped up. Hence most RNA based therapeutics target the liver.

Vaccines are a really great use case, not just a, "we could help out here too," side-case. They're delivered intra-muscularly so there's less "go to the liver!", and the immunogenicity is a feature not a bug.

Lots of this comes from siRNA therapeutic research that is older than mRNA work, but the principles are very similar. Some older articles that touch on some of these issues:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3378126/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3269031/

https://www.sciencedirect.com/science/article/pii/S016836591...

[aden1ne]

Free DNA is not exactly uncommon. Apoptotic cells release DNA into their environment all the time. As another example, free foetal DNA in the mother's bloodstream is how NIP tests can operate.

[entee]

It has very short half life, there’s not a ton of it and it’s likely to be wrapped around a nucleosome. Uniformly, sequences in blood are quite short (<200bp) which is far too small to code for anything meaningful (for reference COVID genome is 29kbp, and the spike protein version in the vaccine is about 4kbp). The bloodstream shreds free DNA pretty effectively, but yes, some short DNA can be detected. That’s a good bit different than a large amount of mRNA/DNA floating around though, especially if it’s a long sequence.

Useful reference:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715266/