Immunostimulant citrus fruit-derived extracellular vesicle nanodrugs for malignant glioma immunochemotherapy

Immunochemotherapy of glioma remains a great challenge due to the poorly immunogenic response. Herein we demonstrate immunostimulant citrus fruit-derived extracellular vesicle (EV) loaded with doxorubicin (DOX)-based nanoparticles to efficiently bypass the blood–brain barrier/blood–brain tumor barrier (BBB/BBTB) to reprogram the immunosuppressive microenvironment, greatly enhancing the anti-tumor efficiency against poorly immunogenic glioma via immunochemotherapy. We have developed four kinds of citrus fruit EVs-based drug delivery systems and the results indicate that lemon-derived EV (LEV) inheriting much more bioactive ingredients (including Vitamin C, Vitamin E and hesperidin) exhibit superior anti-tumor immunity by triggering secondary necrosis. As expected, combined with DOX-induced immunogenic cell death (ICD), efficient immunochemotherapy of glioma can be achieved by lemon-based nanodrugs (LEV-AD). They exhibit excellent capacities for promoting dendritic cells (DCs) maturation, increasing cytotoxic T lymphocytes (CTLs) infiltration and decreasing the regulatory T cells (Tregs) number in the glioma microenvironment, significantly reversing the immunosuppression microenvironment. We believe our immunostimulant citrus fruit-derived EV nanodrugs, integrating natural bioactive ingredients of EVs and chemotherapeutics to synergistically reprogram immunosuppressive tumor microenvironment, provide an alternative avenue for poorly immunogenic tumor immunochemotherapy.