A dual responsive hydrogel with a single-atom copper nanodrug for precision and sustained tumor therapy

Abstract

Conventional tumor therapies such as surgery, radiotherapy, and chemotherapy are often limited by low specificity, systemic toxicity and high recurrence rates. Chemodynamic therapy (CDT), which leverages the tumor microenvironment (TME), has emerged as a promising alternative. However, its efficacy is constrained by the insufficient endogenous hydrogen peroxide (H₂O₂) levels in tumors. To address this, we developed an innovative nanoplatform by integrating a single-atom copper nanozyme (Cu-SAC) into a pH/reactive oxygen species (ROS) dual-responsive in situ-forming hydrogel (Cu-SAC@TP). The Cu-SAC acted as a dual-enzyme mimic. Under weakly acidic TME conditions, it first generated superoxide anions (O₂⁻˙) from oxygen and NADPH, which were subsequently converted to supply H₂O₂. This self-supplied H₂O₂ was then catalyzed by the same Cu-SAC via a Fenton-like reaction to yield highly toxic ROS, including hydroxyl radicals (˙OH) and singlet oxygen (¹O₂). In vitro assays demonstrated that Cu-SAC@TP induced selective cytotoxicity in 4T1 cells by elevating intracellular ROS, promoting lipid peroxidation, and disrupting mitochondrial membrane potential. In a 4T1 tumor-bearing mouse model, Cu-SAC@TP significantly suppressed tumor growth, with the most potent effect observed in the hydrogel group, attributable to the sustained release and localized accumulation of Cu-SAC. This work combines the catalytic prowess of a single-atom nanozyme with a smart hydrogel delivery system, effectively overcoming the key limitations of traditional CDT and presenting a safe, efficient, and sustainable strategy for precision tumor therapy.