Quaternized Poly(vinylpyrrolidone- co -4-vinylpyridine) Copolymers for siRNA Delivery

Abstract Polymers offer a promising alternative to established lipid nanoparticles for therapeutic RNA delivery. Here, we introduce alkyl-chain-quaternized poly(vinylpyrrolidone-co-4-vinylpyridine) copolymers (PVP-co-PVPy) for siRNA delivery, marking their first reported use for this purpose to the best of our knowledge. These polymers are easily synthesized via a two-step synthesis, starting with a free-radical polymerization of two inexpensive monomers, followed by quaternization with an iodoalkane. Formulation involves simple batch mixing in PBS, reproducibly yielding small spherical particles. The functional performance of the polymers as siRNA carriers, assessed by in vitro gene silencing of the enhanced green fluorescent protein (eGFP) reporter gene, as well as their cytotoxicity, both depend on the ratio of the two monomers and the alkyl chain length. The best-performing polymers in this study both feature a decyl chain and monomer ratios of PVP/PVPy between 65/35 and 70/30, achieving eGFP knockdown of 70–80% while maintaining around 70–80% cell viability.