Targeted Degradation of EGFR Mutations via Self-Delivery Nano-PROTACs for Boosting Tumor Synergistic Immunotherapy
Xuechun Wang1, Jie Yan1, Yilei Zhao1
1Shandong Provincial Hospital, Medical Science and Technology Innovation Center, School of Clinical and Basic Medical Sciences, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong 250117, China.
Abstract:
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 in vivo, 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.
Insights
Self-delivery nanoparticles enhance proteolysis targeting chimera (PROTAC) therapy by degrading mutated EGFR and reducing immunosuppression. This combination therapy, integrating PROTACs with photodynamic and immunotherapy, significantly suppressed lung tumors in mice.
Area of Science:
- Nanotechnology and Drug Delivery
- Cancer Therapeutics
- Molecular Biology
Background:
- Proteolysis targeting chimera (PROTAC) therapy shows promise for targeted protein degradation but suffers from poor bioavailability and limited in vivo application.
- Mutated epidermal growth factor receptor (EGFR) is a key driver in many cancers, making it a critical therapeutic target.
- Current PROTAC applications are hindered by hydrophobicity, poor membrane permeability, and nonspecific distribution.
Purpose of the Study:
- To develop self-delivery PROTAC nanoparticles (CP NPs) for efficient degradation of mutated EGFR.
- To integrate photodynamic therapy (PDT) and immunotherapy with PROTAC delivery for enhanced cancer treatment.
- To evaluate the efficacy of CP NPs in a lung cancer mouse model.
Main Methods:
- Development of gefitinib-based PROTACs integrated into nanoparticles (CP NPs) with photosensitizers.
- Assessment of NP tumor accumulation, EGFR degradation, and programmed cell death protein ligand 1 (PD-L1) levels.
- Evaluation of synergistic effects of PROTACs, PDT, and immunotherapy in vivo using a lung cancer mouse model.
Main Results:
- CP NPs enhanced tumor accumulation, leading to selective EGFR degradation and reduced PD-L1 levels, alleviating tumor immunosuppression.
- Laser irradiation triggered potent PDT effects and induced immunogenic cell death, synergizing with PROTACs for an antitumor immune response.
- Significant suppression of primary, distant, and metastatic lung tumors was observed in the mouse model.
Conclusions:
- Nano-PROTACs offer a viable strategy to overcome the bioavailability limitations of traditional PROTACs.
- The developed CP NPs effectively degrade target proteins and facilitate combined photodynamic and immunotherapy.
- This approach holds significant potential for expanding PROTAC applications in advanced cancer therapy.
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