Endoplasmic Reticulum-Targeting Highly Branched Poly(β-amino ester)s for Skin Gene Delivery

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.