Sortilin‐Mediated Rapid, Precise and Sustained Degradation of Membrane Proteins via mRNA‐Encoded Lysosome‐Targeting Chimera
Xin Chang, Xinyu Qiu, Xiaoning Tong, Shaoju Gan, Weicheng Yi, Sitao Xie, Xiangsheng Liu, Chao Zuo, Weihong Tan
Abstract
Abstract Recent advances in lysosome‐targeting degradation technologies have introduced strategies to regulate therapeutic membrane proteins (MPs), potentially transforming treatment paradigms. However, challenges persist, including limited degradation precision due to the broad distribution of lysosome‐targeting receptors (LTRs), as well as the high cost and complexity of recombinant protein production or chemical synthesis. Herein, it identifies sortilin as a promising LTR, highly expressed in malignancies but minimally present in healthy tissues outside the nervous system. Using AlphaFold‐Multimer, it screened for a specific non‐endogenous protein binder to sortilin and developed a modular, mRNA‐encoded lysosomal targeting chimera (MedTAC) strategy, enabling rapid design and precise degradation of oncogenic MPs. In a breast cancer‐bearing mouse model, a single low dose of MedTAC PTK7 (0.5 mg kg −1 ) reduced protein tyrosine kinase‐7 (PTK7) levels by up to 80% within 24 h, with sustained degradation of 44% at 72 h, demonstrating excellent pharmacokinetics. MedTAC PTK7 significantly extended survival to over 50 days without systemic toxicity, compared to 20–30 days in controls. This MedTAC strategy establishes sortilin as a selective and efficient shuttle for targeted protein degradation, offering a scalable, rapidly producible platform for biochemical research and precise therapeutic applications.