Virus-mimetic Gd-Fe nanocarriers co-delivering cisplatin and a TGF-βRI inhibitor induce ferroptosis and sensitize ovarian carcinoma to PD-1 blockade

Virus-mimetic hollow Gd-Fe nanocarriers enable co-delivery of cisplatin and TGF-βRI inhibitor for synergistic chemo-ferroptosis therapy. • The nanoparticle trigger iron-dependent cell death while blocking TGF-β signaling, synergistically suppressing tumor growth. • The nanoparticle overcomes resistance to immune checkpoint therapy by shifting the tumor microenvironment toward an immune-active state. Ovarian carcinoma remains poorly responsive to immune checkpoint blockade, partly because of a TGF-β-enriched and immunosuppressive tumor microenvironment. Here, we developed a virus-mimetic hollow Gd-Fe nanocarrier for the co-delivery of cisplatin (DDP) and the TGF-β receptor I inhibitor TGFβRI-IN-3 (IN-3), aiming to integrate chemotherapy, ferroptosis induction, and TGF-β pathway blockade into a single therapeutic platform. DDP/IN-3@Gd-Fe nanoparticles (NPs) were prepared using a hard-template strategy. Cellular uptake, cytotoxicity, apoptosis, and ferroptosis-associated biochemical changes were evaluated in SKOV3 cells. In tumor-bearing mice, biodistribution, T1-weighted MRI contrast, biosafety, and antitumor efficacy were further investigated. The prepared NPs exhibited uniform size, good stability, and high drug loading with sustained release. In vitro , DDP/IN-3@Gd-Fe NPs were effectively internalized by SKOV3 cells and demonstrated superior cytotoxicity, apoptosis induction, and ferroptosis promotion compared to free drugs. In vivo , DDP/IN-3@Gd-Fe NPs exhibited the strongest tumor growth inhibition, involving synergistic induction of apoptosis and ferroptosis and effective suppression of the TGF-β signaling pathway. Finally, DDP/IN-3@Gd-Fe NPs were found to remodel the immunosuppressive TME by increasing inflammatory mediators and promoting tumor infiltration of cytotoxic T cells and dendritic cells. In conclusion, DDP/IN-3@Gd-Fe NPs provide an MRI-traceable chemo-ferroptosis platform that may attenuate TGF-β-associated immunosuppression and improve checkpoint blockade responses in ovarian carcinoma. Download: Download high-res image (168KB) Download: Download full-size image