An In Vivo Self‐Assembled Bispecific Nanoblocker for Enhancing Tumor Immunotherapy

Abstract

Anti‐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

Self-assembly of peptide nanomaterials at biointerfaces: molecular design and biomedical applications

“…116,117 When the peptide assemblies interact with the hydrophobic membrane core, lipids can condense with self-assembled peptides. 118,119 The increase in membrane fluidity allows lipids to be incorporated into the fibrous structure, effectively lowering the free energy barrier for fibril formation and leading to the formation of lipoprotein clusters. 120 Research shows that the presence of certain membrane components accelerates peptide assembly with a focus on (1) anionic lipids, (2) ganglioside clusters, and (3) the role of the peptide-to-lipid ratio.…”