Mimicking NADPH oxidase and lipoxygenase by using a biodegradable single-site catalyst via a cascade reaction to trigger tumor-specific ferroptosis†

Ferroptosis exhibits promising potential in cancer therapy via lipid peroxidation (LPO) accumulation, while its therapeutic efficacy is normally limited by inadequate ROS production and adverse effects on normal tissues. Here, a TME-activated in situ synthesis of a single-site catalyst (Fe(II)–PW₁₁) is reported, which triggers ferroptosis by mimicking natural enzyme activities of NADPH oxidase (NOX) and lipoxygenase (LOX) via cascade reactions. Upon degradation of the nanocarrier by the overexpressed GSH in an acidic TME, Fe(II)–PW₁₁ is obtained through the coordination of Fe²⁺ into lacunary phosphotungstic acid (PW₁₁). Subsequently, Fe(II)–PW₁₁ catalyzes NADPH depletion and O₂˙⁻ generation through a NOX-like process. This facilitates the formation of high-valent Fe(IV)O–PW₁₁, initiating cascade reactions to generate lipid radicals through hydrogen atom transfer based on LOX-like activity. Thus, Fe(II)–PW₁₁ synergistically accelerates LPO accumulation and antioxidant inhibitions, effectively inducing ferroptosis for cancer therapy. Notably, Fe(II)–PW₁₁ is degraded into low-toxic debris in normal organs, reducing side effects after treatment. Significantly, the whole process is well confirmed by comprehensive characterization studies including online monitoring via ambient mass spectrometry. This work not only reveals a novel ferroptosis-based cancer treatment in a ROS-independent pathway, but also provides a safe therapeutic modality with low toxicity to normal tissues.