Manganese Biomineralized Ferritin Nanoplatforms with Shielding and Stimuli-Responsive Release for Potentiated Ferroptosis and Multimodal Ovarian Cancer Therapy

Purpose: Natural ferritin Fn) is a cage-like protein with a central cavity, making it a promising vehicle for drug delivery. However, its non-specific accumulation in iron-metabolizing organs impairs targeting precision and therapeutic efficacy. To overcome this challenge, we aimed to develop a novel biomimetic nanoplatform based on manganese-mineralized ferritin loaded with dihydroartemisinin (DHA@MFn) for precise ovarian cancer treatment, enabling controlled drug release and amplified therapeutic effects within the tumor microenvironment.Methods: We constructed a manganese-mineralized ferritin nanocage encapsulating DHA, resulting in DHA@MFn with favorable physicochemical properties, including a particle size of 12.2 nm and a zeta potential of − 13.54 mV. The stability, stimuli-responsiveness, and in vitro release behavior of DHA@MFn were evaluated under weakly acidic conditions. We assessed its ability to catalyze Fenton-like reactions releasing Mn2+, induce ferroptosis via lipid peroxidation and GSH depletion, and enable controlled drug release. In vivo biodistribution, tumor accumulation, and therapeutic efficacy were investigated using SKOV3 tumor-bearing mice, alone and in combination with irradiation.Results: DHA@MFn remained stable and demonstrated excellent responsiveness to the tumor microenvironment, releasing Mn2+ ions that catalyzed Fenton-like reactions for hydroxyl radical production. The nanoplatform facilitated targeted tumor accumulation and retention, significantly reducing off-target organ distribution, particularly in the liver. The release of DHA induced ferroptosis through lipid peroxidation and GSH depletion, enhancing oxidative stress. Combined with irradiation, DHA@MFn achieved superior tumor ablation through synergistic ferroptosis, photothermal effects, and minimal systemic toxicity compared to free DHA, MFn alone, or their combinations with irradiation.Conclusion: This multifunctional biomimetic nanoplatform presents a promising strategy for precise, multimodal ovarian cancer therapy. By integrating controlled drug delivery, catalytic Fenton-like reactions, and synergistic radiotherapy, DHA@MFn demonstrates significant potential for clinical translation in targeted cancer treatment.