Recruiting T-cells toward the brain for enhanced glioblastoma chemo-immunotherapy efficacy by co-delivery of cytokines and temozolomide via ultrasound-gated redox-responsive extracellular vesicles

The main limitation of chemo-immunotherapy in glioblastoma (GBM) is the immunosuppressive tumor microenvironment (TME) and the restricted permeability of the blood-brain barrier (BBB). Here, we engineer redox-responsive macrophage-derived extracellular vesicles (M-EVs)-based nanovesicles (TC@MEVs) co-loaded with chemokine CXC chemokine ligand 10 (CXCL10) and temozolomide (TMZ). Combined with ultrasound (US)-mediated BBB opening, TC@MEVs release CXCL10 to recruit CD8⁺ T cells to the GBM region, synergizing with the high concentration of TMZ to amplify the chemo-immunotherapy efficacy of GBM. Consequently, up to 5.52-fold increase in CD8⁺ T cells are observed with US-guided co-delivery of CXCL10 and TMZ, compared to free TMZ and CXCL10. This spatiotemporal combination strategy enhances chemo-immunotherapy by reducing Tregs by 46%, increasing the M1/M2 macrophage ratio by 10.05-fold, achieving 40% tumor elimination, prolonging survival, and establishing long-term immune memory in orthotopic GBM mice. Overall, US-mediated the redox-responsive M-EVs nanovesicles to reverse the immunosuppressive TME by improving the infiltration of CD8⁺ T cells and local release of TMZ, may present a promising strategy for effective GBM chemo-immunotherapy.