Axially Chlorinated Carbon Nanodots for Hypoxia-Tolerant Neutrophil-Mimicking Photoenzymatic Cascade Therapy against...

Neutrophil-mediated enzymatic cascades are critical for pathogen defense and tumor cell eradication. However, mimicking and activating such cascades in therapeutic settings are challenged by the lack of efficient catalytic carriers and the limited availability of superoxide anions (O₂^•-) within tumors and their microenvironments. Here, we report the facile synthesis of axially chlorinated single-atom iron/nitrogen-doped carbon nanodots (Cl-FeNCDs) via a one-step solvothermal method. The Cl-FeNCDs exhibit type I photodynamic activity, enabling efficient O₂^•- generation even under hypoxic conditions to initiate a neutrophil-inspired photoenzymatic cascade. Single-atom Cl-Fe-N₄ coordination confers superoxide dismutase (SOD)-like activity, facilitating endogenous H₂O₂ production, while axial chlorine coordination shifts the H₂O₂ decomposition pathway from homolytic cleavage (yielding ^•OH, POD-like) toward heterolytic cleavage (yielding HClO, MPO-like), thereby enhancing cascade specificity. Encapsulation of Cl-FeNCDs in bovine serum albumin (BSA) yields stable nanocomplexes (CDs@BSA) with robust photodynamic activity under hypoxia. These nanodots effectively induce tumor cell pyroptosis and stimulate antitumor immune responses via neutrophil-mimicking cascades. Moreover, incorporation into an injectable, photo-cross-linkable hydrogel enables in situ cavity filling postsurgery, offering a multifunctional platform to prevent recurrence of triple-negative breast cancer through synergistic photodynamic, enzymatic, and immune activation.