Hollow heterojunction nanocages of zeolitic imidazolate framework-8@zinc sulfide@copper sulfide for synergistic tumor therapy

The tumor microenvironment (TME) poses significant challenges for achieving efficient cancer remission through monotherapy, making multimodal synergistic therapy a key strategy in tumor treatment. Here, we designed and constructed a hollow core–shell nanocage based on zeolitic imidazolate framework-8 (ZIF-8), zeolitic imidazolate framework-8@zinc sulfide@copper sulfide (ZIF-8@ZnS@CuS, denoted as ZZCS), for the combined application of chemodynamic therapy (CDT), photothermal therapy (PTT) and photocatalytic therapy (PCT). The Cu 2+ ions in ZZCS imparted peroxidase (POD)-like and catalase (CAT)-like activities, enabling the generation of toxic hydroxyl radicals ( OH) through POD-like catalysis to enhance CDT effect, while also reacting with overexpressed glutathione (GSH) to elevate intracellular reactive oxygen species (ROS) levels. To overcome the inhibitory effects of hypoxia on PCT in the TME, ZZCS catalyzed the production of O 2 from endogenous hydrogen peroxide (H 2 O 2 ) via CAT-like activity, alleviating hypoxia and enhancing the PCT effect. Furthermore, hollow core–shell heterojunction structure of ZZCS exhibited excellent near-infrared absorption and multiple light reflection effects. Under 808 nm laser irradiation, ZZCS showed a high photothermal conversion efficiency (η = 78.1 %) and generated significant amounts of ROS ( OH, O 2 − , 1 O 2 ), enabling the synergistic elimination of tumor cells via PTT and PCT. Benefiting from the combined CDT/PTT/PCT effects, ZZCS demonstrated excellent therapeutic efficacy in vivo, nearly eradicating tumors. This study may provide a promising foundation and potential direction for advancing multimodal tumor therapy. Future studies will focus on conducting long-term investigations to systematically evaluate the efficacy of ZZCS core–shell nanocages in achieving durable tumor eradication.