Advanced Delivery Systems for Telomere-Targeting Nucleic Acid Therapeutics

Abstract

Nucleic acid therapeutics can provide precise sequence programmability for cancer and aging-related telomeres and telomerase, but their clinical translation is still severely limited due to rapid nuclease degradation, endosomal trapping and mainly the nuclear barrier. This paper systematically reviews the landscape of delivery methods designed to overcome these physiological barriers and seeks to bridge the gap from molecular design in the laboratory to actual in vivo proof of concept in animal models. Foundational chemical changes like Phosphorothioate backbones and Locked Nucleic Acids are seen as crucial for enhancing stability and binding affinity. In addition to this, viral vectors, LNPs (Lipid Nanoparticles), polymeric systems, etc., different kinds of carrier platforms are also analyzed for observing the overall performance of this system to obtain balanced results with regard to efficiency of nuclear transduction, safety, and manufacturing scale. This paper emphasizes focusing on synergy, using “stealth” carriers for systemic circulation with specific nuclear localization signals (NLS) so that the payload is deposited at the chromosomal ends. This paper aims to summarize current progress on the adaptation relationships between delivery routes and telomere-specific demands and to offer a reference on how to choose an appropriate delivery strategy for oncology and regenerative medicine.