A Versatile Strategy to Transform Cationic Polymers for Efficient and Organ‐Selective mRNA Delivery

Abstract The progress of mRNA therapeutics underscores the imperative demand for the development of targeted delivery systems. While cationic polymers hold promise as genetic vectors, their poor in vivo efficacy and numerous variants highlight the urgent need for a universal functionalization strategy to bolster their delivery capabilities. Here, we present a versatile strategy to transform low‐cost commercial cationic polymers into phospholipidated and alkylated polymers (PAPs), enabling efficient and organ‐selective mRNA delivery in vivo. This straightforward post‐functionalization method can be readily broadened to a diverse array of existing cationic polymers, enhancing their cellular uptake, endosomal escape, and mRNA release functionalities. Consequently, PAPs facilitate up to 30,500‐fold higher mRNA expression compared to their unmodified counterparts in vivo. Notably, the one‐component PAPs enable spleen‐specific mRNA delivery, with their vaccine application validated in a mouse melanoma model following intravenous administration. Better still, PAPs can synergize with different helper lipids to formulate four‐component lipid nanoparticles (LNPs), achieving respective lung‐ and liver‐specific mRNA delivery. Noteworthy is that these organ‐selective mRNA delivery systems significantly outperform previous polymer and LNP benchmarks. This transformation strategy for cationic polymers represents a generalized methodology to give highly effective mRNA carriers, highlighting substantial potential for clinical translation of mRNA therapies with organ‐targeting requirements.