Click-constructed modular signal aptamer chimeras enable receptor-independent degradation of membrane proteins

• 成果类型: Article
• 署名作者: Xie, Wanlin; Sun, Weidi; Li, Qin; Dang, Yang; Ma, Lele; Liu, Yuan; Zhang, Hui; Qu, Fengli; Tan, Weihong
• 署名单位: Tianjin University; Zhejiang Cancer Hospital; Chinese Academy of Sciences; Hangzhou Institute of Medicine, CAS
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14297
• DOI: 10.1073/pnas.2424500122
• 发表日期: 2025-05-19
• 关键词: lysosomes; paradigm; as1411

摘要

Cell-membrane proteins are critical mediators of signal transduction, playing essential roles in disease occurrence and progression. The emerging LYTACs (Lysosome-targeting chimeras) technology combines drug-targeting strategies with lysosomal degradation, providing a novel approach to drug development and offering new possibilities for disease therapy. However, the clinical applicability of current LYTAC degraders is limited by the variable expression of lysosome-targeting receptors (LTRs) in tissues. To overcome this limitation, we herein hijacked a YXX & Oslash; sorting signal that derived from lysosome-associated membrane protein 2a (LAMP-2a) to develop a signal aptamer platform (SApt), which exhibits high specificity for targeting membrane proteins and inducing efficient lysosomal degradation. SApts were synthesized by conjugating the YXX & Oslash; signal peptide to the aptamer's terminus through a click reaction. Our study demonstrated that SApts efficiently degrade disease-associated membrane proteins, such as PTK7, Met, and NCL, based on the inherent signals rather than specific LTR. The potent antitumor efficacy of SApts was further confirmed in a xenograft tumor model, where in vivo degradation of PTK7 was observed. Collectively, our work provides insights into the development of a simple and universal lysosomal degradation platform with potential translational value in clinical treatment.