Abstract

Boron neutron capture therapy (BNCT) is an emerging tumor radiotherapeutic modality, but its efficacy is limited by incomplete understanding of tumor cell death mechanisms. Here, we demonstrate that BNCT fails to sufficiently induce ferroptosis—a form of programmed cell death with important implications for both tumor elimination and immune activation—which constrains its therapeutic potential. Using proteomic profiling across multiple tumor cell lines, we found that although BN-triggered mitochondrial dysfunction activated several death-related pathways, robust ferroptosis was not achieved. To address this, we developed a biomimetic nanoagent, m(E@BN), composed of erastin-loaded boron nitride nanosheets coated with tumor cell membranes for targeted delivery. This system significantly enhanced BNCT-induced ferroptosis in vitro and in vivo, synergistically promoting lipid peroxidation and iron metabolism dysregulation without aggravating DNA injury. Furthermore, m(E@BN)-augmented BNCT stimulated potent antitumor immunity, evidenced by increased T cell infiltration and establishment of immune memory. Our study not only elucidates a mechanistic limitation of BNCT but also offers an effective nanomedicine-based strategy to amplify its efficacy through ferroptosis activation, providing a broadly applicable paradigm for improving radiotherapeutic outcomes.