A Macrophage-Driven Multimodal Nanoplatform Conquers Ovarian Cancer Peritoneal Metastasis

Ovarian cancer peritoneal metastasis remains a lethal clinical challenge, with hyperthermic intraperitoneal chemotherapy (HIPEC) offering limited survival benefits due to off-target toxicity, position-dependent delivery, and the lack of durable immune activation. Herein, we report a macrophage-driven precision nanoplatform that enables tumor-homing delivery and multimodal therapeutic synergy. By engineering M1-polarized, tumor-tropic macrophages to deliver mitoxantrone (MTO)-loaded metal-organic framework nanoparticles (MTO NPs@M1), we achieve selective accumulation at peritoneal metastases via the innate homing capacity of macrophages. Upon near-infrared (NIR) irradiation, the system triggers on-demand release of MTO NPs, enabling a trimodal therapeutic strategy: (I) chemotherapy via MTO-induced DNA damage, (II) photothermal ablation, and (III) chemodynamic therapy (CDT) through Cu-MOF-mediated •OH generation. This combined strategy induces strong immunogenic cell death (ICD), promoting dendritic cell maturation and cytotoxic T cell infiltration. Combined with anti-PD-L1 checkpoint blockade, the platform achieves near-complete eradication of peritoneal metastases in murine ovarian cancer and elicits robust adaptive immune memory that prevents recurrence, as confirmed in a tumor rechallenge model. By integrating targeted delivery, multimodal tumor eradication, and immune activation, this strategy addresses the limitations of conventional HIPEC and provides a promising translational approach for ovarian cancer peritoneal metastasis.