InterfaciallyEngineered Hafnium-Doped Hollow PrussianBlue Nanoreactors for Hypoxia-Relieved Synergistic Radio-Chemo-PhotothermalTherapy

Abstract Radiotherapy (RT), a cornerstone of modern oncology, is often hindered by the hypoxic tumor microenvironment (TME), inherent radioresistance, and collateral damage to surrounding healthy tissues. To circumvent these limitations, we developed a biomimetic, interfacially engineered nanoplatform (CMHHND) designed for precision synergistic therapy. The nanoplatform features hafnium-doped hollow Prussian blue (HHPB) nanocatalysts as a functional core, which are loaded with nuclear-targeted doxorubicin and encapsulated within a homologous cancer cell membrane (CM) shell. This macromolecular camouflage grants the system exceptional colloidal stability and superior homotypic targeting capabilities through interfacial molecular recognition. Mechanistically, CMHHND functions as a multimodal agent: it acts as a photothermal agent, a dual-enzyme mimic with catalase (CAT)- and peroxidase (POD)-like activities to modulate the TME, and a radiosensitizer leveraging the high atomic number (Z) of Hf to enhance X-ray deposition. Systematic in vivo experiments confirmed that CMHHND-mediated synergistic therapy (RT/PTT/Chemo) effectively eradicated 4T1 tumors with no apparent systemic toxicity. Our findings highlight that integrating biomimetic interfacial engineering with multifunctional nanocatalysts provides a potent strategy to reverse hypoxia-associated radioresistance, offering a robust paradigm for the design of advanced colloidal nanomedicines in precision cancer therapy.