Engineered nano-delivery platforms targeting ferroptosis-evasion pathways to reverse tumor drug resistance

Tumor multidrug resistance remains a major driver of treatment failure, largely due to the adaptive plasticity that enables cancer cells to evade conventional therapies. Ferroptosis, a non-apoptotic cell-death modality driven by iron-dependent lipid peroxidation, offers a mechanistically distinct route to overcome therapy-resistant tumors. However, until now, there is not any review focus on a systematic framework that links specific ferroptosis-evasion pathways to rational nanocarrier design. To address this gap, we adopt a pathway-centric classification framework, organizing nanocarrier strategies according to the resistance mechanisms they target: iron dysregulation, lipid substrate depletion, multi-compartmental antioxidant hyperactivation, epigenetic regulation by non-coding RNAs, and hypoxia adaptation. We discuss how rationally engineered nanoplatforms restore iron availability, reprogram lipid metabolism, disable antioxidant defenses, remodel the tumor microenvironment, and, crucially, simultaneously block compensatory pathways through multi-target integrated systems. By directly linking resistance mechanisms to nanoplatform design, this review provides an actionable framework for overcoming the adaptive resilience of drug-resistant tumors, offering both mechanistic insights and translational guidance.