Enzyme-like bimetallic nanoclusters modulate tumor microenvironment to enhance radiosensitization for multimodal imaging and synergistic photothermal-radiotherapy.

The synergistic combination of radiotherapy (RT) and photothermal therapy (PTT) holds great promise for cancer treatment, yet its efficacy is severely hampered by tumor hypoxia, insufficient reactive oxygen species (ROS) generation, and lack of precise imaging guidance. Herein, we develop bovine serum albumin (BSA)-biomineralized bimetallic nanoclusters (IrMnOx NCs) that remodel the tumor microenvironment (TME) to enhance radiosensitization while enabling CT/MRI dual-modal imaging-guided radio-photothermal synergistic therapy. The nanoplatform exhibits catalase-like activity to decompose endogenous H2O2 into O2, effectively alleviating hypoxia and overcoming radioresistance, as confirmed by reduced HIF-1α expression in vivo. Meanwhile, the MnOx component depletes glutathione (GSH) and catalyzes Fenton-like reactions, boosting intratumoral ROS levels and augmenting oxidative damage. Upon X-ray irradiation, the high-Z iridium (Ir) enhances local energy deposition, further amplifying RT efficacy. Notably, IrMnOx NCs possess strong near-infrared absorption with a photothermal conversion efficiency of 33.8%, enabling efficient PTT. In the acidic TME, triggered Mn2+ release activates an "OFF-ON" T1-weighted MRI signal (r1 = 6.38 mM-1 s-1), while Ir provides CT contrast (11.96 HU mM-1), allowing precise tumor delineation and real-time therapy monitoring. In 4T1 tumor-bearing mice, intravenous injection of IrMnOx NCs leads to effective tumor accumulation peaking at 4 h post-injection. The combined PTT/RT treatment achieves an 80.07% apoptosis rate and near-complete tumor elimination, without appreciable systemic toxicity or organ damage, as evidenced by histology and blood biochemistry. This TME-responsive bimetallic nanoplatform successfully integrates radiosensitization, multimodal imaging, and PTT, offering a robust strategy for imaging-guided precision cancer therapy.