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

作者：Liu, Shikai; Li, Wenting; Ding, He^*; Tian, Boshi; Fang, Linyang; Zhao, Xudong; Zhao, Ruoxi; An, Baichao; Ding, Lianfei; Zhong, Lei^*; Yang, Piaoping^*

来源：Small, 2023, 19(45).

DOI：10.1002/smll.202303057

• ferroptosis
• nanozymes
• peroxynitrite
• RuO2
• sonodynamic therapy

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 RuO2 exhibit highly efficient singlet oxygen (O-1(2)) generation capacity, which is sequentially amplified by superoxide dismutase and catalase-mimicking activity of RuO2 with hypoxia relief. Meanwhile, the S-nitrosothiol group in BCNR breaks off to release nitric oxide (NO) on-demand, which then reacts with O-1(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.

• 单位
  哈尔滨工程大学; 广东医学院; 哈尔滨医科大学; 南方医科大学