Facile Synthesis of Multifunctional Bioreducible Polymers For mRNA Delivery.

Bioreducible polymeric mRNA carriers are an emerging family of vectors for gene delivery and vaccine development. Several bioreducible systems have been generated through aqueous-phase ring-opening polymerization of lipoic acid derivatives, however this methodology limits the incorporation of hydrophobic functionalities into resulting polymers. Herein we synthesize a poly(active ester)disulfide polymer that can undergo facile aminolysis with amine-containing substrates under stoichiometric control and  mild reaction conditions to yield a library of multifunctional polydisulfide polymers. Functionalized polydisulfide polymer species form stable mRNA-polymer nanoparticles for intracellular delivery of mRNAs in vitro . Alkyl-functionalized polydisulfide-RNA nanoparticles demonstrate rapid cellular uptake and excellent biodegradability when delivering EGFP and OVA mRNAs to cells in vitro . This streamlined polydisulfide synthesis provides a new facile methodology for accessing multifunctional bioreducible polymers as biomaterials for RNA delivery and other applications.