How to address the issue of instability of nucleic acid drugs within the body?

Question

Accepted Answer

Oligonucleotide drugs are unstable in the body, easily degraded by nucleases in circulation, and cleared through the kidneys with a short half-life.

At the same time, exogenous nucleic acid molecules are immunogenic and easily trigger immune reactions in the human body.

In addition, oligonucleotide drugs will not be effective if they cannot enter the cell through endocytosis.

With technological breakthroughs, some problems have been better solved at present, among which chemical modification (such as: phosphate backbone, ribose, ribose five-membered ring modification, base, nucleotide modification, etc.) can avoid the degradation of nucleic acid drugs by nucleases and prolong the half-life.

Efficient and safe delivery systems (such as cyclodextrin nanopolymers, lipid nanoparticles, conjugate delivery systems, acetylgalactosamine systems, etc.) can precisely target nucleic acid drugs to target cells and improve the efficiency of cell uptake, so that nucleic acid drugs can exert therapeutic functions.