Multivalent RGD Peptide-Mediated Nanochimera for Lysosomal Degradation of PDL1 Protein
Yanfei Song1,2, Linjie Cui1,2, Zhilin Liu1
1State Key Laboratory of Polymer Science and Technology, Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China.
Abstract:
The development of immune checkpoint inhibitors, especially PDL1 antibodies, has revolutionized cancer therapy, but the posttherapy recycling of PDL1 proteins poses a significant challenge by inducing resistance and reducing treatment efficacy. To address this, we introduce an integrin-driven, lysosome-targeted nanochimera, composed of poly(glutamic acid), RGD peptides, and PDL1 antibodies, is designed to engage the target PDL1 protein, with the αvβ3 integrin binding to the multivalent RGD peptides to direct the complex through the endocytosomal pathway to the lysosome, ensuring PDL1 degradation and blocking its recycling. Our in vitro and in vivo experiments demonstrate that these nanochimeras potently activate T-cell antitumor immunity by downregulating PDL1 expression within tumor cells and tissues, significantly enhancing the efficacy of PDL1 antibodies. A key discovery of our study is the pivotal role of multivalent RGD peptides in facilitating target protein degradation, providing valuable insights for the development of more efficacious and sophisticated immunotherapies.
Insights
New nanochimeras target and degrade PDL1 proteins, overcoming resistance to cancer immunotherapies. This approach enhances T-cell activity and boosts the effectiveness of PDL1 antibodies for improved cancer treatment.
Area of Science:
- Immunology
- Nanotechnology
- Oncology
Background:
- Immune checkpoint inhibitors, particularly PDL1 antibodies, have transformed cancer therapy.
- Post-therapy recycling of PDL1 proteins leads to treatment resistance and reduced efficacy.
- Developing strategies to prevent PDL1 recycling is crucial for enhancing immunotherapy outcomes.
Purpose of the Study:
- To design and evaluate an integrin-driven, lysosome-targeted nanochimera for PDL1 degradation.
- To investigate the nanochimera's ability to block PDL1 recycling and enhance cancer immunotherapy.
- To elucidate the role of multivalent RGD peptides in facilitating target protein degradation.
Main Methods:
- Construction of a nanochimera comprising poly(glutamic acid), RGD peptides, and PDL1 antibodies.
- Utilizing αvβ3 integrin binding to RGD peptides for endosomal pathway-mediated lysosomal delivery.
- In vitro and in vivo experiments to assess PDL1 downregulation and T-cell activation.
- Evaluation of enhanced efficacy of PDL1 antibodies in combination with the nanochimera.
Main Results:
- The nanochimera successfully targets PDL1 proteins and directs them for lysosomal degradation, preventing recycling.
- Significant downregulation of PDL1 expression in tumor cells and tissues was observed.
- Potent activation of T-cell antitumor immunity and enhanced therapeutic efficacy of PDL1 antibodies.
- Multivalent RGD peptides were identified as critical for facilitating PDL1 degradation.
Conclusions:
- The developed nanochimera effectively overcomes PDL1 recycling-mediated resistance in cancer immunotherapy.
- This approach offers a novel strategy to enhance the efficacy of existing PDL1-based therapies.
- The findings provide valuable insights for designing next-generation immunotherapies targeting protein degradation.
