Nanomaterial-mediated Ferroptosis as a Promising Strategy for Cancer Therapy

Abstract

Conventional cancer therapies, such as chemotherapy and radiotherapy, often face limitations due to drug resistance, systemic toxicity, and tumor heterogeneity, which significantly limit the therapeutic effect. Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation and antioxidant defense collapse, has emerged as a promising approach, particularly for aggressive and therapy-resistant malignancies. However, the clinical application of molecular ferroptosis inducers is hindered by poor pharmacokinetics and off-target effects. Nanotechnology offers a promising solution by enabling targeted delivery and controlled ferroptosis induction.This review provides a critical summary of nanomaterial-mediated ferroptosis, with a focus on lysosome-targeted strategies as the pathological epicenter. First, a critical analysis of the current molecular mechanisms and regulatory networks of nanomaterialmediated ferroptosis was conducted, which can promote targeted delivery and develop cancer treatment methods. Then, we classify and evaluate nano-sensitizers based on their primary mechanism of action, detailing the design principles, structure-activity relationships, and characteristics of both iron-based nanomaterial and non-iron-based nanomaterials. Finally, we summarize the applications of the multifunctional nanoplatform, which can combine ferroptosis induction with existing treatments to improve the therapeutic effect. This review highlights the potential of nanomaterial-mediated ferroptosis as a targeted, effective, and resistance-overcoming paradigm for nextgeneration cancer therapy.