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

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(0.2)Fe(2.8)O(4)@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 T(2)-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.