Biodegradable Hyperbranched Poly(Amine-Co-Ester)-Based Polymeric Nanoparticles for mRNA Delivery

Despite the availability of mRNA vaccines utilizing lipid nanoparticles (LNPs) delivery technology, there remains a pressing need for the development of non-viral messenger ribonucleic acid (mRNA) delivery vectors that are both more efficient and safe. Here, a novel hyperbranched poly(amine-co-ester) (HBPA) system, catalyzed by immobilized lipase, is presented for efficient in vitro and in vivo mRNA delivery. By polymerizing four monomers - pentadecanolactone, sebacic acid, N-methyldiethanolamine, and triethanolamine-HBPA with a controllable hyperbranched structure is successfully synthesized. Subsequent end-group modification with amino compound E results in hyperbranched poly(amine-co-ester) with End group (HBPA-E). Comparative evaluations reveal that HBPA-E outperforms ≈7 times as linear poly(amine-co-ester) (LPA-E) and 3 times the commercial transfection reagent Lipofectamine MessengerMAX (LipoMM) in terms of intracellular delivery efficiency while demonstrating lower cytotoxicity. Furthermore, the in vivo pulmonary delivery efficiency of HBPA-E is 22 times that of LPA-E and the commercial in vivo delivery reagent in vivo-JetRNA, and intranasal delivery also exhibits high efficiency. Finally, the HBPA-E can be easily dissolved in ethanol, and its mRNA formulation can be employed as a freeze-drying formulation, making it a valuable candidate for future clinical applications of mRNA delivery.