Sortilin‐Mediated Rapid, Precise and Sustained Degradation of Membrane Proteins via mRNA‐Encoded Lysosome‐Targeting Chimera

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 MedTACPTK7 (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. MedTACPTK7 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.