Inducing tumor ferroptosis a pH-responsive NIR-II photothermal agent initiating lysosomal dysfunction

Ferroptosis is a unique programmed cell death process that was discovered a few years ago and plays an important role in tumor biology and treatment. However, it still remains a challenge to modulate tumor ferroptosis by spatiotemporally controlled cell-intrinsic Fenton chemistry. Herein, a pH activated photothermal sensitizer IR-PE has been designed and synthesized on the basis of cyanine bearing a diamine moiety, which is capable of triggering the lysosomal dysfunction-mediated Fenton pathway under the irradiation of near-infrared light to evoke ferroptosis, thereby improving antitumor efficacy and mitigating systemic side effects. A pH-responsive molecule that can promote the intrinsic Fenton reaction in tumor cells with NIR light irradiation was developed, and the acid-activatable photothermal properties of IR-PE also exhibited strong antitumor efficacy.