Dual–magnetically driven nanozymes for glioblastoma immunotherapy via magnetothermal and NIR–amplified ferroptosis and apoptosis

Abstract

The hindrance posed by the blood-brain barrier (BBB) and the unique characteristics of the tumor microenvironment (TME) remain major challenges in glioblastoma (GBM) therapy. Here, we developed a dual-magnetically driven ultrasmall Mo_0.2Fe_2.8O₄@CeO_x/FA (MFCF) nanozyme exhibiting multienzyme catalytic activities for targeted synergistic therapy of GBM. This nanozyme demonstrated dual responsiveness to alternating magnetic fields (AMF) and static magnetic fields, synergized with folic acid (FA)–mediated molecular targeting to enhance BBB penetration and achieve high-precision GBM localization. Upon simultaneous exposure to AMF and near-infrared (NIR) laser irradiation, MFCF amplified reactive oxygen species (ROS) generation, depleted glutathione, and alleviated hypoxia through synergistic magnetothermal effects, type-II photodynamic therapy, and its intrinsic multienzyme catalytic activities, ultimately inducing both ferroptosis and apoptosis. Notably, this hybrid cell-death pathway triggered immunogenic cell death, promoting the proliferation and differentiation of T cells and thereby achieving systemic immune activation. Concurrently, it reprogrammed M2-polarized macrophages into pro-inflammatory M1 phenotypes, remodeling the immunosuppressive TME and enhancing antitumor immunotherapy. Furthermore, the excellent superparamagnetism of MFCF enabled T₂-weighted magnetic resonance imaging (MRI)-guided treatment monitoring. Overall, this work presents a multifunctional nanoplatform that overcomes BBB and TME barriers to enable precise, immunomodulatory therapy for GBM.