Endoplasmic Reticulum-Targeting Highly Branched Poly(β-amino ester)s for Skin Gene Delivery
Chenfei Wang, Wei He, Rui Guo, Chaolan Pan, Haiyang Yong, Tao Bo, Yitong Zhao, Zhili Li, Feifei Wang, Weiyi Xu, Dingjin Yao, Si Zhang, Ming Li, Dezhong Zhou
Abstract
Gene therapy has emerged as a promising strategy for treating various hereditary cutaneous disorders. However, the entrapment of nucleic acids in endosomes is a significant hurdle. Here we synthesized endoplasmic reticulum (ER)-targeting highly branched poly(β-amino ester)s (ER-HPAEs) and investigated their potential for skin gene delivery. The incorporation of methyl-benzenesulfonamide (NMS) moieties endowed ER-HPAEs with a strong ER-targeting ability, allowing ER-HPAE/DNA polyplexes to bypass the conventional endosomal pathway and facilitate nuclear internalization. The optimized ER-HPAEs exhibited high transfection efficiency and biocompatibility across multiple cell types, surpassing the performance of Lipofectamine 3000 (Lipo3000). Intriguingly, the ER-HPAEs can effectively deliver plasmids to mediate high-levels of transglutaminase 1 ( TGM1 ), membrane-bound transcription factor peptidase site 1 ( MBTPS1 ), and collagen type VII alpha 1 chain ( COL7A1 ) expression both in vitro and in vivo . This study establishes a strategy for synthesizing HPAEs with ER-targeting ability and identifies potential candidates for skin gene delivery.