l-Arginine-Modified CoWO₄ /FeWO₄ S-Scheme Heterojunction Enhances Ferroptosis against Solid Tumor

Ferroptosis has recently attracted much attention as an anti-tumor therapy. Evidence suggests that ferroptosis can induce oxidative stress and accumulation of lethal lipid peroxides in cancer cells, leading to cell damage. However, unsuitable pH, H₂ O₂ levels, and high glutathione (GSH) expression in the tumor microenvironment hinder the development of ferroptosis-mediated therapy. In this study, an l-arginine (l-arg)-modified CoWO₄ /FeWO₄ (CFW) S-scheme heterojunction is strategically designed and constructed for ultrasound (US)-triggered sonodynamic- and gas therapy-induced ferroptosis. CFW not only has excellent Fenton-catalytic activity, outstanding GSH consumption capacity, and excellent ability to overcome tumor hypoxia, but its S-scheme heterostructure can also avoid the rapid combination of electron (e) and hole (h⁺ ) pairs, thereby enhancing the sonodynamic effects. As a precursor of nitric oxide (NO), l-arg is modified on the surface of CFW (CFW@l-arg) to achieve controlled NO release under US irradiation, thereby enhancing ferroptosis. In addition, poly(allylamine hydrochloride) is further modified on the surface of CFW@l-arg to stabilize l-arg and achieve controllable NO release. Both in vitro and in vivo results demonstrate that such a multifunctional therapeutic nanoplatform can achieve high therapeutic efficacy through sonodynamic and gas therapy-enhanced ferroptosis. This designed oncotherapy nanoplatform provides new inspiration for ferroptosis-mediated therapy.