Rationally Engineering Pro‐Proteins and Membrane‐Penetrating α‑Helical Polypeptides for Genome Editing Toward Choroidal Neovascularization Treatment

IF 27.4 1区 材料科学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Xun Liu, Ziyin Zhao, Wei Li, Mengyao Ren, Haoyu Zhang, Desheng Cao, Yehan Wang, He Yang, Yajie Li, Manhui Zhu, Laiqing Xie, Lichen Yin
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引用次数: 0

Abstract

Ribonucleoprotein (RNP)‐based CRISPR/Cas9 genome editing holds great potential for the treatment of choroidal neovascularization (CNV), which however, is challenged by the lack of efficient cytosolic protein delivery tools. Herein, reversibly‐phosphorylated pro‐proteins (P‐proteins) with conjugated adenosine triphosphate (ATP) tags are engineered and coupled with a membrane‐penetrating, guanidine‐enriched, α‐helical polypeptide (LGP) to mediate robust and universal cytosolic delivery. LGP forms salt‐stable nanocomplexes (NCs) with P‐proteins via electrostatic interaction and salt bridging, and the helix‐assisted, strong membrane activities of LGP enabled efficient cellular internalization and endolysosomal escape of NCs. Therefore, this approach allows efficient cytosolic delivery of a wide range of protein cargoes and maintains their bioactivities due to endolysosomal acidity‐triggered traceless restoration of P‐proteins. Notably, intravitreally delivered LGP/P‐RNP NCs targeting hypoxia‐inducible factor‐1α (HIF‐1α) induce pronounced gene disruption to downregulate pro‐angiogenic factors and alleviate subretinal fibrosis, ultimately provoking robust therapeutic efficacy in CNV mice. Such a facile and versatile platform provides a powerful tool for cytosolic protein delivery and genome editing, and it holds promising potential for the treatment of CNV‐associated diseases, such as age‐related macular degeneration.
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来源期刊
Advanced Materials
Advanced Materials 工程技术-材料科学:综合
CiteScore
43.00
自引率
4.10%
发文量
2182
审稿时长
2 months
期刊介绍: Advanced Materials, one of the world's most prestigious journals and the foundation of the Advanced portfolio, is the home of choice for best-in-class materials science for more than 30 years. Following this fast-growing and interdisciplinary field, we are considering and publishing the most important discoveries on any and all materials from materials scientists, chemists, physicists, engineers as well as health and life scientists and bringing you the latest results and trends in modern materials-related research every week.
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