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

• Published in: Chemical engineering journal (Lausanne, Switzerland : 1996) Switzerland : 1996), 2024-03, Vol.484, p.149463, Article 149463
• Main Authors: Li, Jinheng, Wang, Xuejiao, Guo, Haoyan, Zhou, Houwang, Sha, Suinan, Yang, Yulu, Chen, Jianping, Hao, Xiangrong, Pan, Jiahao, Wang, Ying, Fan, Jun-Bing
• Format: Article
• Language: English
• Subjects: Biomimetic nanodrugs; Citrus fruit-derived extracellular vesicle; Glioma immunochemotherapy; Hesperidin; Immunogenic cell death; Secondary necrosis
• ISSN: 1385-8947; 1873-3212
• DOI: 10.1016/j.cej.2024.149463

•The bioactive ingredients of citrus fruit EV can induce secondary necrosis to produce anti-tumor immunity.•Citrus fruit EV nanodrugs enable to enhance the anti-glioma immunochemotherapy efficacy.•Citrus fruit EV nanodrugs can reverse the immunosuppressive glioma microenvironment. 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.