Viscosity-dependent photocatalysis triggers ferroptosis and Type-I photodynamic therapy to kill drug-resistant tumors

• A smart CF 3 - CVJ NPs with tumors viscosities responsiveness was prepared via one-pot method. • CF 3 - CVJ NPs exhibited excellent photocatalytic and type I PDT efficacy with the release of SO 2 , ·CF 3 , and ∙O 2 – . • The elevated lipid peroxides by ·CF 3 and ∙O 2 − and inactivated GPX4 by SO 2 co-induced ferroptosis. • The CF 3 - CVJ NPs killed drug-resistant tumor cells via a ferroptosis-apoptosis synergistic modality. Treating complex drug-resistant tumors is a challenge in clinical practice. Ferroptosis, a unique form of programmed cell death, is a promising therapeutic strategy to address such tumors. We present a method by which a photodynamic and photocatalytic synergy triggered ferroptosis to kill drug resistant tumors via a triarylmethane/CF 3 SO 2 Na-based liposomal nanosystem (CF 3 - CVJ NPs). Under 630-nm light irradiation, the type-I photosensitizer, CVJ , catalyzed the persistent conversion of O 2 to ∙O 2 − and CF 3 SO 2 Na to ·CF 3 and SO 2 . Thereafter, the generated ·CF 3 efficiently oxidized lipids to lipid peroxides together with ∙O 2 − and induced ferroptosis in drug-resistant cells, while SO 2 inhibited the catabolic lipid peroxidation enzyme glutathione peroxidase 4. Our results revealed that photosensitized reactions upregulated pro-apoptotic proteins through mitochondrial damage, resulting in the reactivation of drug-resistant tumor cell apoptosis. The efflux of the photosensitizer, CVJ , was prevented by reducing efflux protein expression as well as mitochondrial adenosine triphosphate production. Overall, utilizing arginine-glycine-aspartic acid (RGD)-tumor targeting and the different viscosities between tumor cells and normal cells, is our new strategy for treating drug-resistant tumors, with excellent selectivity and efficiency.