Ferroptosis has received ever-increasing attention due to its unparalleled mechanism in eliminating resistant
tumor cells. Nevertheless, the accumulation of toxic
lipid peroxides (LPOs) at the
tumor site is limited by the level of
lipid oxidation. Herein, by leveraging versatile
sodium alginate (ALG)
hydrogel, a localized ferroptosis trigger consisting of
gambogic acid (GA), 2,2'-azobis [2-(2-imidazolin-2-yl)
propane] dihydrochloride (AIPH), and Ink (a photothermal agent), was constructed via simple intratumor injection. Upon 1064 nm
laser irradiation, the stored AIPH rapidly decomposed into alkyl radicals (R•), which aggravated LPOs in
tumor cells. Meanwhile, GA could inhibit
heat shock protein 90 (HSP90) to reduce the heat resistance of
tumor cells, and forcefully consume
glutathione (GSH) to weaken the
antioxidant capacity of cells. Systematic in vitro and in vivo experiments have demonstrated that synchronous consumption of GSH and increased
reactive oxygen species (ROS) facilitated reduced expression of
glutathione peroxidase 4 (GPX4), which further contributed to disruption of intracellular redox homeostasis and ultimately boosted ferroptosis. This all-in-one strategy has a highly effective
tumor suppression effect by depleting and generating fatal active compounds at
tumor sites, which would pave a new route for the controllable, accurate, and coordinated
tumor treatments.