Nanoparticle-Mediated Ferroptosis for Cancer Therapy: Mechanisms and Therapeutic Strategies

Marzena Szwed, Anastazja Poczta-Krawczyk, Karol Bukowski, Agnieszka Marczak Department of Medical Biophysics, Institute of Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, Lodz, 90-236, PolandCorrespondence: Marzena Szwed, University of Lodz, 141/143 Pomorska Street, Lodz, 90-236, Poland, Email [email protected]: Ferroptosis, an iron-dependent form of regulated cell death, is increasingly leveraged in nanomedicine to sensitise tumours and overcome drug resistance. Driven by the Fenton reaction, ferroptosis results in lipid peroxidation through elevated intracellular iron levels and excessive production of reactive oxygen species (ROS). In this review, we outline the molecular markers of ferroptosis and define the criteria necessary to attribute ferroptosis induction to nanoparticles (NPs). We emphasise the importance of distinguishing targeted ferroptosis from non-specific ROS-mediated nanotoxicity and other types of programmed cell death. This distinction requires the use of lipophilic radical-trapping antioxidants (eg, ferrostatin-1, liproxstatin-1), iron chelators, and evidence implicating glutathione peroxidase 4 (GPX4) or the system Xc− antiporter. Morphology is considered supportive but non-diagnostic, requiring converging evidence from both biochemical and genetic sources. We then compare various nanosystems designed to induce ferroptosis, such as iron-based nanoparticles, lipid nanocarriers, light-triggered nanoparticles, and magnetically induced nanocarriers, highlighting mechanistic patterns, efficacy determinants, and common pitfalls that often occur during biological investigations. Finally, we discuss translational challenges, including tumour microenvironment heterogeneity, NP protein corona dynamics, clearance and off-target effects. We aim to provide a framework that links NP design to ferroptotic mechanisms and clinically relevant outcomes, offering clear criteria and priorities for future research. Keywords: nanoparticles, regulated cell death, nanomedicine, iron ions, oxidative stress