Multivalent RGD Peptide-Mediated Nanochimera for Lysosomal Degradation of PDL1 Protein
Yanfei Song, Linjie Cui, Zhilin Liu, Zhaohui Tang, Xuesi Chen
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 α v β 3 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.