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

Abstract 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.