Lysosome-targeting chimeras (LYTACs) represent a promising approach for the targeted degradation of membrane proteins. Currently, two primary methods for LYTAC development involve chemically modified antibodies and wild-type insulin-like growth factor 2 (IGF2) fusion proteins (iLYTACs). However, LYTACs necessitate intricate chemical modification processes, while wild-type IGF2 in iLYTAC technology binds to IGF1R, potentially triggering carcinogenesis. To tackle this challenge, we introduce specific IGF2R-binding lysosomal targeting chimeras (sLYTACs), a novel technology utilizing engineered IGF2 mutant fusion antibodies for the degradation of endogenous membrane proteins. Diverging from iLYTACs, sLYTACs exhibit selective binding to IGF2R with increased affinity, significantly bolstering the anti-proliferative impact on drug-resistant tumor cells both in vitro and in vivo. By effectively degrading third-generation tyrosine kinase inhibitor-resistant EGFR mutants, masking binding epitope HER2, and concurrently targeting compensatory receptors interacting with these proteins, sLYTACs show great promise in drug development to overcome bypass signaling and combat drug resistance in tumors.