Microenvironment-triggered copper peroxide and tannic acid cooperatively iron-coordinated nanocomposites for oxidative stress-enhanced radiotherapy of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and aggressive forms of liver cancer, with limited treatment options and poor prognosis. The effectiveness of conventional radiotherapy (RT) is often hindered by tumor cell resistance and damage to surrounding healthy tissues. To address this challenge, this study introduces a novel hydrogen peroxide (H 2 O 2 ) self-supplying copper peroxide (CuO 2 )-iron-tannic acid (Fe-TA) nanocomposite aiming to enhance the efficacy of oxidative stress-enhanced RT for HCC. The CuO 2 nanoparticles (CP) component functions as an H 2 O 2 self-supplying platform, releasing H 2 O 2 and Cu 2 + in the acidic tumor microenvironment (TME), thereby generating hydroxyl radicals (•OH) endogenously through Fenton-like reactions. Additionally, the iron ions released from this nanocomposite amplify Fenton catalysis, thus reducing reliance solely on copper-based nanomaterials . The iron ions also facilitate magnetic resonance (MR) imaging to guide RT. A series of in vitro and in vivo experiments demonstrate that the CuO 2 @Fe-TA nanocomposites (CPF) can controllably and selectively inhibit tumor growth when activated by the TME and X-ray irradiation. Moreover, comprehensive toxicity assessments confirm that the prepared CPF exhibit good biocompatibility and safety. This research offers a clinically viable sensitizer for liver RT of HCC and suggests potential implications for the treatment of other cancer types. A novel H 2 O 2 self-supplying copper peroxide-iron-tannic acid nanocomposite has been developed to enhance the efficacy of oxidative stress-enhanced radiotherapy for hepatocellular carcinoma. • This is the first time that a microenvironment-responsive H 2 O 2 self-supplying nanocomposite is designed for HCC radiotherapy. • Selective inhibition of liver tumor growth can be achieved via Fenton-like reaction catalyzed by CPF as a radiosensitizer. • The CPF can enhance MR imaging, thereby improving guidance during RT by ensuring optimal tumor spatial distribution. • The CPF exhibit good biocompatibility and safety.