Recruiting T‐Cells toward the Brain for Enhanced Glioblastoma Immunotherapeutic Efficacy by Co‐Delivery of Cytokines and Immune Checkpoint Antibodies with Macrophage‐Membrane‐Camouflaged Nanovesicles

• Published in: Advanced materials (Weinheim) 2023-06, Vol.35 (25), p.e2209785-n/a
• Main Authors: Xu, Xiaoxuan, Zhang, Zhiqi, Du, Jiawei, Xue, Yonger, Chen, Xin, Zhang, Jianqiong, Yang, Xue, Chang, Di, Xie, Jinbing, Ju, Shenghong
• Format: Article
• Language: English
• Subjects: Antibodies; blood–tumor barrier; Brain; CXCL10; Effectiveness; glioblastoma multiforme; immune checkpoint inhibitors; immunosuppressive microenvironment; Immunotherapy; Ligands; Materials science; Membranes; nanovesicles; Recruitment; Tropism; Tumors
• ISSN: 0935-9648; 1521-4095
• DOI: 10.1002/adma.202209785

Immunotherapy with immune checkpoint inhibitors (CPIs) shows promising prospects for glioblastoma multiforme (GBM) but with restricted results, mainly attributed to the immunosuppressive tumor microenvironment (TME) and the limited antibody permeability of the blood–tumor barrier (BTB) in GBM. Here, nanovesicles with a macrophage‐mimicking membrane are described, that co‐deliver chemotactic CXC chemokine ligand 10 (CXCL10), to pre‐activate the immune microenvironment, and anti‐programmed death ligand 1 antibody (aPD‐L1), to interrupt the immune checkpoint, aiming to enhance the effect of GBM immunotherapy. Consequently, the tumor tropism of the macrophage membrane and the receptor‐mediated transcytosis of the angiopep‐2 peptide allow the nanovesicle to effectively cross the BTB and target the GBM region, with 19.75‐fold higher accumulation of antibodies compared to the free aPD‐L1 group. The CPI therapeutic efficacy is greatly enhanced by CXCL10‐induced T‐cells recruitment with significant expansion of CD8+ T‐cells and effector memory T‐cells, leading to the elimination of tumor, prolonged survival time, and long‐term immune memory in orthotopic GBM mice. The nanovesicles, that relieve the tumor immunosuppressive microenvironment by CXCL10 to enhance aPD‐L1 efficacy, may present a promising strategy for brain‐tumor immunotherapy. Nanovesicles with a macrophage‐mimicking membrane, co‐delivering chemoattractant CXCL10 and immune checkpoint inhibitor aPD‐L1 to orthotopic glioblastoma multiforme (GBM), are developed to pre‐activate the immune microenvironment, thereby enhancing anti‐PD‐L1 therapy efficacy. This work provides a paradigm for GBM immunotherapy that enhances brain accumulation of aPD‐L1 and avoids the negative impact of the immunosuppressive microenvironment of malignant tumors.