Bioorthogonal oncolytic-virus nanovesicles combined bio-immunotherapy with CAR-T cells for solid tumors.

Various oncolytic viruses (OVs) have been adopted as therapeutic tools to increase the efficacy of chimeric antigen receptor (CAR)-T cells against solid tumors. However, the therapeutic effect of OVs has been limited by pre-existing neutralizing antibodies and poor targeting delivery for systemic administration. Herein, we propose using bioorthogonal OV nanovesicles to boost the antitumor effects of CAR-T cells in solid tumors by reshaping the tumor microenvironment. Using a cell-membrane nanomimetic technique, we embedded artificial chemical ligands on cancer cell surfaces and then encapsulated lysoviral particles to obtain dual-targeted OV nanovesicles with bioorthogonal targeting and homologous recognition. OVs can be directly encapsulated into cancer cell nanovesicles and exhibit a liposome-like nanostructure, efficient loading, and excellent tumor-targeting capability. Encouragingly, OV nanovesicles efficiently induced tumor-cell apoptosis while sparing normal tissues and cells, thereby inhibiting tumor growth. Administration of viral nanovesicles effectively increased the secretion of anti-tumor cytokines such as IL-2, TNF-α and IFN-γ, and significantly promoted the infiltration and activation of CD8⁺CAR-T cells in tumors. Our data suggest that bioorthogonal OV nanovesicles hold great potential to overcome the limitations of CAR-T cells as monotherapies against solid tumors and, thus, drive the clinical application of combination therapy.