Homologous magnetic targeted immune vesicles for amplifying immunotherapy via ferroptosis activation augmented photodynamic therapy against glioblastoma

Abstract

In spite of noteworthy breakthroughs in clinical treatments, immune checkpoint blockade (ICB) therapy is often hindered by T lymphocyte dysfunction in the immunosuppressive microenvironment of glioblastoma (GBM). Herein, GBM-derived exosomes (GBM-Exos) co-encapsulate ferroptosis inducer arsenic trioxide (ATO) and NIR photosensitizer IR780, modified with superparamagnetic iron oxide nanoparticle (SPION), to construct homologous magnetic targeted immune vesicles (Sp-Exo/AI) for reinvigorating anti-tumor immunity. SPION modified GBM-Exos display capacities of tumor accumulation and blood-brain barrier penetration. Notably, reactive oxygen species metabolism is disturbed by ferroptosis activation augmented photodynamic therapy (PDT), hence triggering tumor cell lysis and mitochondrial damage to reshape tumor microenvironment (TME) and transform GBM from immune “cold” to “hot”. Accordingly, the tumor specific T lymphocytes function and phenotype transformation of macrophages were promoted to stimulate robust innate and adaptive immunities. Significantly, the remarkable ferroptosis activation augmented PDT combining with programmed death-1 antibody actives long-term immune memory and inhibits distal tumor metastasis. Superior anti-tumor effect of Sp-Exo/AI in the recurrence model, breast cancer model and patient-derived model were observed as well. Altogether, the presented homologous magnetic targeted immune vesicles exhibit substantial potential for amplifying immune response in “cold” tumors like GBM through revising immunosuppressive TME.