Exosome-encapsulated CuPt-S hybrid nanoclusters: Triple enzyme activities for cuproptosis-enhanced low-dose...

As a novel form of regulated cell death, cuproptosis holds considerable promise in reversing tumor therapy resistance. However, its application is severely limited by the hypoxic tumor microenvironment (TME), glutathione (GSH)-dependent copper chelation, and off-target toxicity. Similarly, conventional low-doses radiotherapy struggles to achieve high treatment efficacy. Herein, we developed exosome-encapsulated CuPt-S hybrid nanoclusters (EM-CPS) to boost enzymatic activity, address these limitations, and enhance low-dose radiotherapy via cuproptosis. To address the problems of insufficient electron transfer and low therapeutic efficacy, sulfur hybridization was employed to engineer abundant copper valence states and ion pairs (Cu⁰/Cu⁺/Cu²⁺ and Pt⁰/Pt²⁺), thereby fundamentally endowing EM-CPS with efficient triple enzyme-mimetic activities (catalase, peroxidase, glutathione oxidase). Meanwhile, to reduce the nonspecific cytotoxicity of inorganic nanoclusters and improve tumor targeting and immune evasion, exosome membranes were strategically engineered onto the nanocluster surfaces via a co-incubation approach, thereby fabricating a novel biomimetic nanoplatform. The nanozyme EM-CPS can significantly modulate TME and influence metabolism. Catalase-like activity alleviated hypoxia by converting H₂O₂ to O₂, promoting lipoylated protein oligomerization. Peroxidase-like activity generated reactive oxygen species to enhance radiosensitivity. Glutathione oxidase-like activity depleted GSH to prevent copper chelation. Notably, low-dose radiotherapy not only causes direct damage to cancer cells but also more significantly serves as a potent inducer of cuproptosis. This biomimetic nanoplatform achieves potent tumor suppression at low radiation doses, offering a precise and safe cancer therapeutic strategy.