Endoplasmic\nReticulum-Targeting Highly Branched Poly(β-amino\nester)s for Skin Gene Delivery

Gene therapy has emerged as a promising strategy for\ntreating various\nhereditary cutaneous disorders. However, the entrapment of nucleic\nacids in endosomes is a significant hurdle. Here we synthesized endoplasmic\nreticulum (ER)-targeting highly branched poly(β-amino ester)s\n(ER-HPAEs) and investigated their potential for skin gene delivery.\nThe incorporation of methyl-benzenesulfonamide (NMS) moieties endowed\nER-HPAEs with a strong ER-targeting ability, allowing ER-HPAE/DNA\npolyplexes to bypass the conventional endosomal pathway and facilitate\nnuclear internalization. The optimized ER-HPAEs exhibited high transfection\nefficiency and biocompatibility across multiple cell types, surpassing\nthe performance of Lipofectamine 3000 (Lipo3000). Intriguingly, the\nER-HPAEs can effectively deliver plasmids to mediate high-levels of\ntransglutaminase 1 (<i>TGM1</i>), membrane-bound transcription\nfactor peptidase site 1 (<i>MBTPS1</i>), and collagen type\nVII alpha 1 chain (<i>COL7A1</i>) expression both <i>in vitro</i> and <i>in vivo</i>. This study establishes\na strategy for synthesizing HPAEs with ER-targeting ability and identifies\npotential candidates for skin gene delivery.