A Tumor-Specific Membrane Protein Degradation Platform via Covalent Reaction-Induced Aggregation

The majority of lysosome-targeting degradation strategies for membrane proteins rely on recruiting specific lysosome-targeting receptors; however, the low expression levels of these receptors in tumor cells limit their further applications. Herein, we design covalent membrane protein aggregate-targeting chimeras, termed CMPATACs, for tumor-specific membrane protein degradation, which do not rely on specific receptors. We first utilized a covalent reaction to irreversibly bind specific membrane proteins, and this process facilitates the formation of membrane protein aggregates that enter the lysosome for degradation, leading to improved anticancer capacity. The wide range of applications of the CMPATAC strategy were demonstrated by degrading broad-spectrum membrane proteins, such as HER2, EGFR, EphA2, and the undruggable ALP, providing a potential way for degrading cell-surface proteins in cancer therapy.