Nanorobots hold PD-L1 and break membrane of colorectal cancer cells for immunotherapy

Abstract

Limited immune cell infiltration is the main reason for poor immunotherapeutic efficacy in colorectal cancer patients. Here we design a peptide-based nanorobot that recognizes PD-L1 and breaks cancer cell membranes by in situ forming fibrils through a pH-responsive module. The nanorobot shows long retention in targeted tumours (>120 h) through interaction with PD-L1 and blocks PD-1/PD-L1 to activate the T cell killing effect. At the same time, in the tumour microenvironment (pH 6.5), it forms fibrils that break the cancer cell membrane, inducing immunogenic cell death with the release of damage-associated molecular patterns and the subsequent infiltration of T cells. The nanorobot shows higher therapeutic efficacy than the regimen of αPD-L1+oxaliplatin in a variety of colorectal-cancer-tumour-bearing mouse models and has good biocompatibility due to the targeted breakage of cancer cells, exhibiting great potential for colorectal cancer immunotherapy in clinic. A peptide-based PD-L1-targeted nanorobot disrupts cancer cell membranes via pH-responsive fibril formation, and enhances T cell infiltration and immune activation, inducing a potent anticancer response in animal models of colorectal cancer.