Ginsenoside Rg3-engineered exosomes as effective delivery platform for potentiated chemotherapy and photoimmunotherapy of glioblastoma

Despite incremental advances in the therapeutic approach to glioblastoma (GBM), patient prognosis is still dismal. Nano-based immunotherapy of therapeutic biomolecules shows promising potential for improvement of GBM immunotherapy. In this work, a ginsenoside Rg3 (Rg3)-functionalized biomimetic nanoplatform is fabricated by encapsulating arsenic trioxide (ATO) and chlorin e6 (Ce6) into exosomes, denoted as Rg3-Exo/ATO@Ce6, to ameliorate photoimmunotherapy via reprogramming the tumor microenvironment (TME). Rg3-Exo/ATO@Ce6 actively penetrates the blood–brain barrier (BBB) and targets GBM via Rg3-mediated transcytosis by binding to glucose transporter 1 overexpressed on both BBB and GBM cells. After shuttling into GBM cells, the released ATO induces highly effective chemotherapy, and the generation of reactive oxygen species from Ce6 upon laser irradiation triggers photodynamic therapy-induced immunogenic cell death. Rg3-Exo/ATO@Ce6 could induce tumor-associated macrophages (TAMs) polarization and increase the M1/M2 TAMs ratio to modulate the immunosuppressive TME. The in vivo results indicate that Rg3-Exo/ATO@Ce6 notably inhibits orthotopic GBM growth, induces TAMs polarization, and facilitates cytotoxic T lymphocytes infiltration, achieving remarkably improved survival benefits. Our study provides a promising strategy to guide the design of engineering endogenous biomimetic nanoplatform for overcoming the biological barriers and integrating combination treatment for tumor therapy.