Nucleic acid drug and delivery techniques for disease therapy: present situation and future prospect (1/2024)

Abstract

RNA molecules hold many properties that facilitate their application as therapeutic drugs. RNAs could fold to form complex conformations to bind to proteins, small molecules, or other nucleic acids, and some even form catalytic centers. Protein-encoding RNAs are the carriers of genetic information from DNA to ribosomes, and various types of non-coding RNAs cooperate in the transcription and translation of genetic information through various mechanisms. To date, three mainstream RNA therapies have drawn widespread attention: 1) messenger RNA (mRNA) that encodes therapeutic proteins or vaccine antigens; 2) small interfering RNA (siRNA), microRNA (miRNA), antisense nucleonic acid (ASO) that inhibit the activity of pathogenic RNAs; 3) Aptamers that regulate protein activity. Here, we summarized the current research and perspectives of RNA therapies, which may provide innovative highlights for cancer therapy. The lipid nanoparticles (LNP) are commonly composed of four components including ionizable lipids, neutral helper phospholipids, cholesterol, and PEGylated lipids. In relative acidic environment, the ionizable cationic phospholipids carries a positive charge and realize electrostatic complexation with negatively charged mRNA molecules to form complex and improve mRNA stability. Upon attachment, the cationic phospholipids fuse with negatively charged cell membranes, trigger membrane destabilization, and promote mRNA molecule delivery. After internalization into cells, the more acidic environment and hydrolases in lysosomes protonate and destroy the bilayer structure of LNP and release mRNA. LNPs can also be expelled from the cell via opposite exocytosis, which is also a concern for mRNA administration via LNPs.