Fe³⁺-DOX-mediated self-assembled nanolipids for tumor microenvironment activated synergistic ferroptotic-chemo therapy assisted with MR-imaging

Chemotherapy is often plagued by side-effects, development of drug resistance, difficulty of targeted delivery, and limited effectiveness. Here, we tackle these issues by rationally designing a nanolipid system with the capabilities of selective accumulation in tumor tissues, responsiveness to tumor microenvironment (TME), synergistic combination of chemotherapy with ferroptosis, magnetic resonance (MR) imaging to monitor the uptake kinetics and therapeutic process. Specifically, a tumor-responsive nanolipid encapsulated with Fe³⁺-DOX nanocomplexes is devised. DOX is only released inside the tumor cells and subsequently induces apoptosis after the nanolipids are selectively accumulated in tumor tissues, readily uptaken by tumor cells, and finally disassembled by overexpressed glutathione (GSH). Free Fe²⁺ ions reduced from Fe³⁺ by GSH catalyze the excess H₂O₂ in tumor cells into cytotoxic ·OH radicals, which in turn cause lipid peroxidation and consequently ferroptosis. Intracellularly released Fe³⁺-DOX nanocomplexes emit strong MR signal, indicating successful internalization of the therapeutics and initiation of the ferroptotic-chemotherapy. Such MR imaging-monitored, highly targeted, synergistic therapy offers high therapeutic efficacy, low side-effects, and immunity to drug resistance.