Self-propelled Ferroptosis Nanoinducer for Enhanced Cancer Therapy

Ferroptosis is a recently proposed type of programmed cell death, associated with a variety of diseases including tumors. Researchers have thereby presented nanoplatforms to mediate ferroptosis for anti-cancer therapy. However, the development of ferroptosis-based nanotherapeutics was hindered by the limited penetration depth in tumors, poor active pharmaceutical ingredient loading content (API) and the systemic toxicity. Herein, self-propelled ferroptosis nanoinducers composed of two endogenous proteins, glucose oxidase and ferritin, are presented to show enhanced tumor inhibition via ferroptosis while remaining high API and biocompatibility. The accumulation of our proteomotors at tumor regions is facilitated by the active tumor-targeting effect of ferritin. The enhanced diffusion of proteomotors is then actuated by efficiently decomposing glucose into gluconic acid and H2O2, leading to deeper penetration and enhanced uptake into tumors. Under the synergistic effect of glucose oxidase and ferritin, the equilibrium between ROS and GSH was damaged, leading to lipid peroxidation. As a result, by inducing ferroptosis, our self-propelled ferroptosis nanoinducers exhibit enhanced tumor inhibition with negligible systemic toxicity. This work paves a way for constructing a biocompatible cancer treatment paradigm with enhanced diffusion utilizing only two endogenous proteins, centered around the concept of ferroptosis.