Hyaluronic acid coating of poly(β-amino ester)/mRNA polyplexes enables ultra-high transfection efficiency

mRNA holds significant potential for a wide range of biomedical applications, efficient and safe delivery of mRNA into target cells is essential to realize its therapeutic benefits. Linear poly(beta-amino ester)s (LPAEs) have been utilized for mRNA delivery, yet there is a need to enhance their transfection efficiency and safety profile. In this study, a novel LPAE-based ternary mRNA delivery system with ultra-high transfection efficiency is developed by coating hyaluronic acid (HA) onto LPAE/mRNA binary polyplexes. Results demonstrate that across a broad range of HA doses, mRNA transfection and cell viability can be significantly enhanced. Intriguingly, pre-treating cells with HA further boosts the transfection efficiency up to 99.2 %. Mechanistic studies reveal that HA coating impacts the size, Zeta potential of the binary polyplexes, enhancing their interaction with the cell membrane and facilitating cellular uptake. Leveraging the unique biocompatibility and biodegradability of HA, this ternary mRNA delivery system emerges as a promising option for practical applications. The approach of coating binary polyplexes with natural biomacromolecules can be extended to other non-viral mRNA delivery vectors to achieve superior transfection efficiency and safety profiles.