In Vivo Self‐Assembled Bispecific Nano‐Blocker for Enhancing Tumor Immunotherapy

Abstract

AbstractAnti‐PD‐L1 monoclonal antibody (mAb) has achieved substantial success in tumor immunotherapy by T‐cells activation. However, owing to the excessive accumulation of extracellular matrix (ECM) components induced unsatisfactory T‐cells infiltration and poor tumor penetration of antibodies makes it challenging to realize efficient tumor immunotherapy. Herein, we reported a peptide‐based bispecific nano‐blocker (BNB) strategy for in situ construction of CXCR4/PD‐L1 targeted nanoclusters on the surface of tumor cells that capable of boosting up T‐cells infiltration through CXCR4 blockage and enhancing T‐cells activation by PD‐L1 occupancy, ultimately realizing high‐performance tumor immunotherapy. Briefly, the BNB strategy selectively recognize and bond CXCR4/PD‐L1 with deep tumor penetration, which rapidly self‐assembles into nanoclusters on the surface of tumor cells. Compared to the traditional bispecific antibody, BNB exhibits an intriguing metabolic behavior, i.e., the elimination half‐life (t1/2) of BNB in the tumor is 69.3 h that is about 50‐time longer than that in the plasma (1.4 h). The higher tumor accumulation and rapid systemic clearance overcomes potential systemic side effect. Moreover, the solid tumor stress generated by excessive extracellular matrix components is substantially reduced to 44%, which promotes T‐cells infiltration and activation for immunotherapy efficacy. Finally, our findings substantially strengthen and extend clinical applications of PD‐1/PD‐L1 immunotherapy.This article is protected by copyright. All rights reserved