Resveratrol-modified polyethyleneimine as a high-efficiency and biocompatible gene delivery vector for enhanced transfection

A critical challenge in advancing gene therapy lies in developing safe and efficient gene delivery vectors. While polyethyleneimine (PEI) demonstrates superior DNA condensation capacity as a non-viral vector, its clinical application is hindered by inherent cytotoxicity. To address these challenges, this study presents a novel gene delivery system utilizing natural polyphenol resveratrol (Res) as a cross-linker through its hydroxyl groups capable of interacting with the amino groups in PEI by chemical modification. Three resveratrol-modified PEI (Res-P600, Res-P1800 and Res-P10k) polymers were synthesized and structurally validated by FTIR and 1 H NMR. The gene delivery efficacy of Res-PEI was rigorously examined through in vitro assessments, focusing on DNA condensation capacity, DNA protection ability and cytotoxicity. Concurrently, the particle size, zeta potential, cell uptake efficiency and transfection efficiency of the Res-PEI/DNA polyplexes were quantitatively characterized. Experimental data revealed that Res-PEI/DNA polyplexes effectively shielded genetic material against enzymatic degradation while demonstrating rapid cellular uptake in 293T cells. Cytotoxicity evaluations confirmed Res-PEI's improved biosafety profile relative to conventional PEI polymers. Notably, Res-P10k demonstrated superior transfection efficiency (78.96 % at w/w = 1) in 293T cells which was closed to lipo 6000. Data from HeLa cells align with our original findings in 293T cells, demonstrating broader applicability. Collectively, these findings position Res-PEI polyplexes as a biocompatible and effective alternative for next-generation gene delivery systems.