Precision chemical synthesis of PEGylated IGF2 for potent and selective lysosomal degradation of transmembrane proteins.

We report a site-specific PEGylation strategy to stabilize insulin-like growth factor 2 (IGF2) as a functional ligand for insulin-like growth factor 2 receptor (IGF2R)-based lysosome-targeting chimera (LYTAC) systems. This chemical modification improves ligand folding and solubility, enabling efficient LYTAC-mediated epidermal growth factor receptor (EGFR) degradation across multiple cell lines and significant tumor suppression (∼70%) in vivo with favorable safety. This study provides a general chemical approach for ligand optimization in lysosome-targeted protein degradation, providing new ideas for the future development of peptide drugs.