Drug delivery has long been a major technical barrier in mRNA drug development. The rapid advancement of mRNA technology relies on interdisciplinary collaboration across biology, medicine, pharmacy, materials science, and chemistry. Numerous innovative material-based solutions have been developed for efficient mRNA delivery.

Non-viral vectors utilize the physicochemical properties of non-viral carrier materials to mediate mRNA delivery. Compared to viral vectors, they offer low toxicity, low immunogenicity, high cargo capacity, broad material sources, controllable chemical structures, and ease of large-scale production. Several non-viral delivery systems have been developed to facilitate cellular uptake of mRNA drugs and protect them from degradation.

Protamine – a natural cationic protein – complexes negatively charged mRNA molecules into nanoscale particles, protecting mRNA from serum RNases. However, protamine binds mRNA too tightly, limiting protein expression efficiency.

Polymer-based delivery systems (PPs) use cationic polymers to self-assemble with mRNA via electrostatic interactions into polyelectrolyte complexes. Common polymers include polylysine (PLL), polyethylenimine (PEI), PAMAM dendrimers, chitosan, and oligopeptides. Advantages include low immunogenicity and modifiable structures to reduce toxicity or enhance membrane interaction.

Lipid-based carriers are currently the most effective non-viral vectors for mRNA delivery. These include lipoplexes (LP) , lipopolyplexes (LPR) , and Lipid Nanoparticles (LNP) . Cationic liposomes were the first liposomal delivery materials for mRNA vaccines. Positively charged liposomes complex with negatively charged mRNA to form multilamellar lipoplexes, protecting encapsulated mRNA from RNase degradation.

LNP is currently the most advanced delivery system—stable nanoparticles composed of ionizable lipids, helper lipids, cholesterol, and PEG-lipids forming a lipid bilayer shell with an aqueous core that carries mRNA. LNPs are readily taken up by antigen-presenting cells and are used by the three major mRNA vaccine companies: Moderna, BioNTech, and CureVac.

Ongoing innovation to overcome current limitations will continue to advance vector delivery and RNA therapeutics toward the ultimate goal of benefiting patients.