Polymerization-Induced Electrostatic Self-Assembly Enables Noncytotoxic Polyplex Formation for Gene Delivery

Abstract Gene delivery is a cornerstone of both basic research and gene therapy, where it holds the key to treating genetic disorders at their source. However, it does not adhere to one-size-fits-all solutions. Cargo-tailored and time-saving approaches are urgently needed for different applications. Photoinduced electron/energy transfer reversible addition-fragmentation chain-transfer (PET-RAFT) polymerization is a technique that enables the synthesis of a wide range of well-defined polymers, allowing for rapid reaction condition screening in small volumes. In this work, polymerization-induced electrostatic self-assembly (PIESA) based on PET-RAFT polymerization is demonstrated to facilitate the simultaneous synthesis and assembly of pDNA polyplexes for transfection. The as-prepared polyplexes are shown to be less cytotoxic than their conventionally assembled counterparts and act as more effective gene delivery vehicles in transfection trials. This strategy provides a versatile platform that facilitates rapid screening of cell-compatible copolymer nanoparticle compositions for gene delivery in ultralow volumes.