Toxic mechanisms of nanoparticle-induced ferroptosis and current research challenges: a critical review

Nanoparticles show exceptional promise in antimicrobials, targeted drug delivery, cancer therapy, and bioimaging due to their unique physicochemical properties. However, their expanding use raises significant toxicity concerns, particularly their ability to induce ferroptosis-an iron-dependent cell death pathway-now recognized as a key mechanism of nanoparticle-induced toxicity in normal tissues, which constitutes the primary focus of this review. Crucially, while nanoparticle-triggered ferroptosis holds therapeutic potential for tumors, its unintended activation in healthy cells represents a major biosafety challenge that requires systematic evaluation. Growing evidence reveals that nanoparticle-induced ferroptosis develops through a cascade of events beginning with combined iron dysregulation and oxidative stress, ultimately triggering fatal lipid peroxidation. The contribution of inflammation remains debated, though recent findings suggest nanoparticle-stimulated inflammatory responses could accelerate ferroptosis by intensifying redox imbalance. While these mechanistic relationships are increasingly understood, the research field remains hampered by unintegrated data that creates both duplication in experimental efforts and significant voids in identifying crucial molecular regulators. To address these limitations, this review critically analyzes current research on nanoparticle-induced ferroptosis, identifying methodological challenges while proposing standardized assessment frameworks and targeted strategies. We further elaborated on the influence of the physicochemical properties of nanoparticles on the induction of ferroptosis, highlighting the critical role of structure-activity relationship studies in deciphering nanomaterial-ferroptosis interactions, thereby providing a basis for accurately assessing their toxicity risks.