Self-assembled nano-activator constructed ferroptosis-immunotherapy through hijacking endogenous iron to intracellular positive feedback loop

Ferroptosis had shown huge potential for antitumor treatment due to its capacity of improving the limited efficiency of traditional antitumor strategies. On the other hand, low confidence in clinical application prospects impeded their development as a result of use of toxic-dose iron. Herein, we prepared a nano-activator (DAR) which was assembled by doxorubicin (DOX), tannic-acid (TA) and IR820 as a photosensitizer to make full use of endogenous iron stored in endo -lysosome, realizing ferroptosis and its related oxidative stress through artificially intracellular positive feedback loop. Interestingly, this process could also promote immunogenic cell death (ICD)-associated immunotherapy through endoplasmic reticulum (ER) stress. After DAR +  laser treatment, the intracellular oxidative stress response was intensified. The produced ROS could be effectively distributed in intracellular lysosomes and ERs to facilitate ferroptosis and immunotherapy respectively. The pharmacodynamics study revealed that DAR + laser had excellent antitumor combination therapy efficiency even under the adverse combined drug ratio of DOX and IR820 due to the unique synergism activation effect of DAR mediated ferroptosis-immunotherapy. In summary, our study provided an innovative solution for the development of antitumor treatment based on ferroptosis-immunotherapy.