X‐Ray‐Triggered CA IX Inhibition Nanoplatform Promotes Intratumoral Acidosis‐Induced Cancer Ferroptosis

Abstract Radiotherapy‐induced ferroptosis is accompanied by an adaptive response to the expression of tumor cell ferroptosis suppressor genes. Herein, a degradable and in situ generated silicomanganese composite system loaded with carbonic anhydrase (CA IX) inhibitor (4‐(2‐aminoethyl) benzenesulfonamide (ABS) is constructed to form a DSiMn‐ABS nanosystem to improve the ferroptosis sensitivity of hypoxic tumor cells and improve the radiotherapy effect. The system can be continuously degraded in the tumor environment and X‐rays, releasing Manganese dioxid （MnO 2 )and ABS; Thereby inhibiting the activity of CA IX, inducing acidification inside tumor cells, regulating the AMP‐activating protein kinase (AMPK)/Acetyl‐CoA carboxylase(ACC) axis to increase the sensitivity of tumor cells to ferroptosis, and depleting glutathione (GSH) through MnO 2 influencing glutathione peroxidase 4 (GPX4) activity, which further inhibits the ferroptosis defense system of tumor cells, and ultimately effectively improves the therapeutic efficiency of radiotherapy. Ultimately, the system can effectively inhibit tumor growth. Therefore, this degradable system can utilize double‐sensitized radiotherapy to provide new ideas for tumor radiotherapy.