Effective Degradation of Wild‐Type and Mutant EGFR Using Self‐Assembling Peptide‐Derived PROTAC Nanoparticles (NanoTACs) for Cancer Therapy

Abstract Epidermal growth factor receptor (EGFR)‐targeted therapeutics, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), have achieved clinical success but are limited by drug resistance and off‐target toxicity. Herein, self‐assembling peptide‐derived PROTAC nanoparticles (NanoTACs) engineered for effective degradation of both wild‐type and mutant EGFR for cancer therapy is reported. The NanoTACs are constructed from three peptide components: EGFR‐binding peptide (EHGAMEI), a self‐assembling peptide linker (FF), and an E3 ligase recruiting peptide (ALAPYIP). Through the hydrophobic interaction and π – π stacking, self‐assembling peptide‐derived PROTACs formed uniform spherical nanoparticles with an average diameter of 144 nm under aqueous conditions. In vitro, NanoTACs effectively eliminated both wild‐type and L858R/T790M‐mutant EGFR in cancer cells through direct lysosomal degradation and PROTAC‐driven proteasomal degradation. In vivo, NanoTACs exhibited 2.24‐fold higher tumor‐targeting efficiency than free EGFR‐binding peptide via the enhanced permeability and retention (EPR) effect and EGFR‐mediated active targeting. In colon and lung tumor models, NanoTACs suppressed tumor growth by 88.3%, achieved 95% degradation of wild‐type and 80% of mutant EGFR, and induced extensive apoptosis without systemic toxicity. These findings established NanoTACs as a promising EGFR‐targeted platform to overcome drug resistance to mAbs and TKIs by enabling effective degradation of wild‐type and mutant EGFR in heterogeneous cancers.