Triple-modal visualized radiohydrogel alleviates post-embolization hypoxia via stage-type procedure in hepatocellular carcinoma.

Transarterial radioembolization (TARE) holds significant potential for hepatocellular carcinoma (HCC), but its effectiveness is hindered by radiation resistance from the post-embolization hypoxic microenvironment and challenges in achieving stable local release of radionuclides. Herein, polydopamine (PDA)-coated MnO2 nanoparticles (MnO2@PDA) with a core-shell structure were introduced as the intratumoral hydrogen peroxide nanocatalyst, and 177Lu was anchored in catechol groups on the PDA surface, achieving the stability of radionuclides. And the radionuclide-coordinated nanocatalyst was incorporated into the poly(ethylene oxide) and poly(propylene oxide) thermosensitive hydrogel to formulate an integrated TARE agent (177Lu-MnO2@PDA-Gel), facilitating secondary encapsulation and ensuring intratumoral retention of radionuclides without leakage. Through a three-stage lytic process, 177Lu-MnO2@PDA-Gel produced oxygen by gradually consuming endogenous H2O2. This allowed for post-embolization radiosensitivity and anti-angiogenesis. Furthermore, the release of manganese ions from the embolic hydrogel can serve as an adjuvant to boost intratumoral immune infiltration and improve the efficacy of embolization and internal radiation. Notably, the superiority of SPECT/PAI/MRI triple-modal imaging via 177Lu-MnO2@PDA-Gel enables real-time and dynamic visualization of TARE. Overall, the smart hydrogel demonstrates long-term oxygen generation, stable internal radiation, and tumor microenvironment remodeling, offering a sequential radiosensitization strategy to address TARE refractoriness, thereby presenting significant clinical value for locoregional therapy of HCC.