Biomineralized RuO2 Nanozyme with Multi‐Enzyme Activity for Ultrasound‐Triggered Peroxynitrite‐Boosted Ferroptosis

Abstract Ferroptosis, as a non‐apoptotic cell death pathway, has attracted increasing attention for cancer therapy. However, the clinical application of ferroptosis‐participated modalities is severely limited by the low efficiency owing to the intrinsic intracellular regulation pathways. Herein, chlorin e6 (Ce6) and N ‐acetyl‐ l ‐cysteine‐conjugated bovine serum albumin‐ruthenium dioxide is elaborately designed and constructed for ultrasound‐triggered peroxynitrite‐mediated ferroptosis. Upon ultrasound stimulation, the sonosensitizers of Ce6 and RuO 2 exhibit highly efficient singlet oxygen ( 1 O 2 ) generation capacity, which is sequentially amplified by superoxide dismutase and catalase‐mimicking activity of RuO 2 with hypoxia relief. Meanwhile, the S ‐nitrosothiol group in BCNR breaks off to release nitric oxide (NO) on‐demand, which then reacts with 1 O 2 forming highly cytotoxic peroxynitrite (ONOO − ) spontaneously. Importantly, BCNR nanozyme with glutathione peroxidase‐mimicking activity can consume glutathione (GSH), along with the generated ONOO − downregulates glutathione reductase, avoiding GSH regeneration. The two‐parallel approach ensures complete depletion of GSH within the tumor, resulting in the boosted ferroptosis sensitization of cancer cells. Thus, this work presents a superior paradigm for designing peroxynitrite‐boosted ferroptosis sensitization cancer therapeutic.