Genetically Programmable Vesicles for Enhancing CAR‐T Therapy against Solid Tumors

Chimeric antigen receptor-T (CAR-T) cell therapy has shown remarkable success in eradicating hematologic malignancies; however, its efficacy in treating solid tumors has always been limited due to the presence of an immune-suppressive tumor microenvironment (TME). Here, genetically programmable cellular vesicles expressing high-affinity anti-programmed death-ligand 1 single chain variable fragment (anti-PD-L1 scFv) loaded with glutamine antagonist (D@aPD-L1 NVs) are developed to metabolically dismantle the immunosuppressive TME and enhance the efficiency of anti-mesothelin CAR-T cells in orthotopic lung cancer. As anti-PD-L1 scFv can specifically bind to the programmed death-ligand 1 (PD-L1) on tumor cells, D@aPD-L1 NVs enable the targeted delivery of glutamine antagonists to the tumor site and address the upregulation of PD-L1 on tumor cells, which prevents the premature exhaustion of CAR-T cells. More importantly, D@aPD-L1 NVs effectively reduce the number of immunosuppressive cells and promote the recruitment of inflammatory cells and the secretion of inflammatory cytokines in tumor tissues. These unique features of D@aPD-L1 NVs improve the infiltration and effector functions of CAR-T cells, which ultimately enhance the anti-tumor ability and long-term memory immunity of CAR-T cells. The findings support that D@aPD-L1 NVs act as a promising drug to strengthen the effectiveness of CAR-T cells against solid tumors.