Rational Nanomaterial Design for Ferroptosis Modulation: Bidirectional Therapeutic Strategies in Cancer and Beyond

Abstract Ferroptosis, a unique form of regulated, iron-dependent cell death, has emerged as a therapeutic mechanism for a range of diseases, including cancer, neurodegeneration, metabolic disorders, and organ injuries. However, the clinical translation of small-molecule ferroptosis modulators remains limited due to poor specificity, pharmacokinetic instability, and insufficient targeting capability. In contrast, nanomaterials offer a highly tunable and multifunctional platform for ferroptosis modulation, enabling precise delivery, spatiotemporal control, and synergistic therapeutic effects. This review presents a comprehensive synthesis of nanomaterial-based strategies for ferroptosis modulation, emphasizing both induction in cancer therapy and inhibition in non-cancer diseases. We first summarize the molecular mechanisms governing ferroptosis and rational design strategies for nanomaterials targeting ferroptosis-related pathways. We then discuss recent advances in nanomaterial-mediated ferroptosis induction for cancer therapy, and their application of ferroptosis inhibition for treating non-cancer diseases, including inflammatory organ injuries, neurological disorders, and metabolic degeneration. By systematically linking nanomaterial molecular and structural design with ferroptosis regulation mechanisms, this review highlights the dual regulatory role of nanomaterials in both inducing and inhibiting ferroptosis and provides design guidelines for the rational development of ferroptosis-targeting nanomedicines for precision therapy.