Functionalized Fe-Doped Carbon Dots Exhibiting Dual Glutathione Consumption to Amplify Ferroptosis for Enhanced Cancer Therapy.

Nonapoptotic ferroptosis is a promising cancer treatment which offers a solution to the multidrug resistance of conventional apoptosis-induced programmed cancer cell death therapies. Reducing intracellular glutathione (GSH) is essential for inducing excess ROS and has been considered a crucial process to trigger ferroptosis. However, treatments reducing GSH alone have not produced satisfactory effects due to their restricted target. In this regard, FeCDs (Fe3+-modified l-histidine -sourced carbon dots) with dual GSH-consumption capabilities were constructed to engineer ferroptosis by self-amplifying intratumoral oxidative stress. Carbon dots have the ability to consume GSH, and the introduction of Fe3+ can amplify the GSH-consuming ability of CDs, reacting with excess H2O2 in the tumor microenvironment to generate highly oxidized •OH. This is a novel strategy through synergistic self-amplification therapy combining Fe3+ and CDs with GSH-consuming activity. The acid-triggered degradation material (FeCDs@PAE-PEG) was prepared by encapsulating FeCDs in an oil-in-water manner. Compared with other ferroptosis-triggering nanoparticles, the established FeCDs@PAE-PEG is targeted and significantly enhances the consumption efficiency of GSH and accumulation of excess iron without the involvement of infrared light and ultrasound. This synergistic strategy exhibits excellent ferroptosis-inducing ability and antitumor efficacy both in vitro and in vivo and offers great potential for clinical translation of ferroptosis.