Advancing Small Nucleic Acid Drug Delivery: From Stability Challenges to Novel Therapeutic Applications

Small nucleic acids (sNA) are revolutionizing several therapeutic environments in areas such as oncology as well as rare disease states. However, despite the progress in RNA modification, lipid nanoparticles (LNPs), and GalNAc conjugation methods, issues like toxicity, immunogenicity, and stability limitations affect the application. Compared with viral and non-viral systems, LNPs have become more credible carriers to solve the problems of RNA degradation and realize more innovation, such as the first RNA interference drug, Patisiran. Likewise, methods for GalNAc conjugation have enabled liver-targeting therapies with better pharmacokinetic profiles. Relative to this subject, novel strategies such as exosome-mediated delivery and multifaceted systems involving LNP-GalNAc and exosome all hold more specificity and biostability. Some of the recent advancements in RNA chemical modifications involve the application of 1-methylpseudouridine which enhances the stability of the RNA and also reduces its immunogenic outcomes. Also, the application of AI in therapeutic areas includes establishing the delivery vectors, estimating severe side effects, and designing new nucleic acid therapies. In addition to hepatic targeting, tissue targetability is now being investigated for other purposes. A solution to the existing stability and targeting limitations is critical for the further development and enhanced use of sNA therapies in broad diseases, including chronic and complex diseases. The major focus of this review is on the recent development and potential future trends of sNA as a drug delivery system for precision medicine.