Multivalent RGD Peptide-Mediated Nanochimera for LysosomalDegradation of PDL1 Protein

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_vβ₃ 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 <i>in vitro</i> and <i>in vivo</i> 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.