Development of Diselenide-Containing Poly(β-amino ester)s for Potent mRNA Delivery to the Spleen.

Polymer-based nanocarriers hold promise for nucleic acid delivery, yet the clinical translation of mRNA polymeric carriers remains hindered by insufficient delivery efficiency and cytotoxicity. Here, we synthesized 180 diselenide-containing poly(β-amino ester)s (PBAEs) via Michael addition. In vitro screening identified PBAEs with superior mRNA delivery efficiency, showing that hydrophobic amine backbones with ionizable cationic amine end-capping are critical. The effective mRNA-PBAE polyplex nanoparticles (PNPs) exhibited moderate positive charge, suitable size, potent cellular uptake, and endosomal escape. Compared with analogs lacking diselenide bonds, diselenide-containing PBAEs demonstrated robust redox responsiveness and formed PNPs with similar mRNA binding and size, but reduced internal hydrophobicity and improved cellular uptake, mediating potent mRNA delivery. Tail vein injection of diselenide-containing PNPs achieved robust splenic-targeted delivery in mice without helper lipids, unlike the lung-targeted delivery of conventional PBAEs. These findings highlight a novel diselenide-containing PBAE platform for effective mRNA delivery, which has great potential in mRNA-based immunotherapeutic applications.