Harmonizing the Intracellular Kinetics toward Effective Gene Delivery Using Cancer Cell-Targeted and Light-Degradable Polyplexes

The success of nonviral gene delivery is often restricted by the multiple cellular barriers that posed inconsistent requirements for vector design. High molecular weight (MW) and cationic charge density are required for polycations to enable effective gene encapsulation, which, however, also lead to high toxicity, restricted intracellular cargo release, and poor serum resistance. We herein developed cross-linked polyethylenimine (PEI) with built-in UV-responsive domains (NP-PEI), which can effectively condense DNA while rapidly de-crosslink upon light triggers to promote intracellular DNA release and reduce material toxicity. HA coating of the polyplexes further enhanced their serum stability by shielding the surface positive charges and enabled cancer cell targeting to potentiate the transfection efficiencies. Thus, the polyplexes afforded high transfection efficiencies in serum upon light irradiation, outperforming PEI 25k by 1-2 orders of magnitude. This study therefore provides a useful strategy to overcome the critical barriers against nonviral gene delivery.