Targeted Degradation of EGFR Mutations via Self-Delivery Nano-PROTACs for Boosting Tumor Synergistic Immunotherapy.

Proteolysis targeting chimera (PROTAC) has recently emerged as a promising strategy to selectively degrade target proteins in the treatment of various diseases. However, it has low bioavailability due to strong hydrophobicity, poor membrane permeability, and nonspecific distribution , which greatly limits its application. In this study, self-delivery PROTAC nanoparticles (designated as CP NPs) integrating gefitinib-based PROTACs and photosensitizers were developed to efficiently degrade mutated epidermal growth factor receptor (EGFR), a crucial kinase for cell growth and survival, while simultaneously triggering photodynamic therapy and immunotherapy. The prepared NPs enhanced the tumor accumulation of PROTACs, which led to the selective degradation of EGFR mutations and a reduction in programmed cell death protein ligand 1 levels, thereby alleviating tumor immunosuppression and immune tolerance. Moreover, under laser irradiation, the coloaded photosensitizers triggered potent photodynamic therapy effects and induced immunogenic cell death, which worked synergistically with PROTACs toward eliciting a robust antitumor immune response. In a mouse model of lung cancer, primary, distant, and lung metastatic tumors were significantly suppressed. This work highlights the potential of nano-PROTACs for degrading target proteins and facilitating combination photodynamic immunotherapy toward expanding PROTAC applications in cancer therapy.