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

IF 8.7 1区化学 Q1 MATERIALS SCIENCE, MULTIDISCIPLINARY ACS Materials Letters Pub Date : 2024-10-11 DOI:10.1021/acsmaterialslett.4c01830

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* and Dezhong Zhou*,

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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.

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用于皮肤基因递送的内质网靶向高支链聚（β-氨基酯

基因疗法已成为治疗各种遗传性皮肤疾病的一种前景广阔的策略。然而，核酸在内质体中的禁锢是一个重大障碍。在这里，我们合成了内质网（ER）靶向高支化聚（β-氨基酯）（ER-HPAEs），并研究了它们在皮肤基因递送方面的潜力。甲基苯磺酰胺（NMS）分子的加入赋予了ER-HPAEs强大的ER靶向能力，使ER-HPAE/DNA多聚体能够绕过传统的内体途径，促进核内化。优化后的ER-HPAEs在多种细胞类型中表现出较高的转染效率和生物相容性，其性能超过了Lipofectamine 3000（Lipo3000）。耐人寻味的是，ER-HPAEs能有效地传递质粒，在体外和体内介导转谷氨酰胺酶1（TGM1）、膜结合转录因子肽酶位点1（MBTPS1）和胶原蛋白Ⅶ型α1链（COL7A1）的高水平表达。这项研究确立了合成具有ER靶向能力的HPAEs的策略，并确定了皮肤基因递送的潜在候选物。

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来源期刊

ACS Materials Letters MATERIALS SCIENCE, MULTIDISCIPLINARY-

CiteScore

14.60

自引率

3.50%

发文量

261

期刊介绍： ACS Materials Letters is a journal that publishes high-quality and urgent papers at the forefront of fundamental and applied research in the field of materials science. It aims to bridge the gap between materials and other disciplines such as chemistry, engineering, and biology. The journal encourages multidisciplinary and innovative research that addresses global challenges. Papers submitted to ACS Materials Letters should clearly demonstrate the need for rapid disclosure of key results. The journal is interested in various areas including the design, synthesis, characterization, and evaluation of emerging materials, understanding the relationships between structure, property, and performance, as well as developing materials for applications in energy, environment, biomedical, electronics, and catalysis. The journal has a 2-year impact factor of 11.4 and is dedicated to publishing transformative materials research with fast processing times. The editors and staff of ACS Materials Letters actively participate in major scientific conferences and engage closely with readers and authors. The journal also maintains an active presence on social media to provide authors with greater visibility.

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