Trends in the synthetic polymer delivery of RNA.

ABSTRACT

Ribonucleic acid (RNA) has emerged as one of the most promising therapeutic payloads in the field of gene therapy. There are many unique types of RNA that allow for a range of applications including vaccination, protein replacement therapy, autoimmune disease treatment, gene knockdown and gene editing. However, RNA triggers the host immune system, is vulnerable to degradation and has a low proclivity to enter cells spontaneously. Therefore, a delivery vehicle is required to facilitate the protection and uptake of RNA therapeutics into the desired host cells. Lipid nanoparticles have emerged as one of the only clinically approved vehicles for genetic payloads, including in the COVID-19 messenger RNA vaccines. While lipid nanoparticles have distinct advantages, they also have drawbacks, including strong immune stimulation, complex manufacturing and formulation heterogeneity. In contrast, synthetic polymers are a widely studied group of gene delivery vehicles and boast distinct advantages, including biocompatibility, tunability, inexpensiveness, simple formulation and ease of modification. Some classes of polymers enhance efficient transfection efficiency, and lead to lower stimulation of the host immune system, making them more viable candidates for non-vaccine-related applications of RNA medicines. This review aims to identify the most promising classes of synthetic polymers, summarize recent research aimed at moving them into the clinic and postulate the future steps required for unlocking their full potential.