NIR‐Actuated Ferroptosis Nanomotor for Enhanced Tumor Penetration and Therapy

Ferroptosis nano-inducers have drawn considerable attention in the treatment of malignant tumors. However, low intratumoral hydrogen peroxide level and complex biological barriers hinder the ability of nanomedicines to generate sufficient reactive oxygen species (ROS) and achieve tumor penetration. Here a near-infrared (NIR)-driven ROS self-supplying nanomotor is successfully designed for synergistic tumor chemodynamic therapy (CDT) and photothermal therapy (PTT). Janus nanomotor is created by the asymmetrical modification of polydopamine (PDA) with zinc peroxide (ZnO₂) and subsequent ferrous ion (Fe²⁺) chelation via the polyphenol groups from the PDA, here refer as ZnO₂@PDA-Fe (Z@P-F). ZnO₂ is capable of slowly releasing hydrogen peroxide (H₂O₂) into an acidic tumor microenvironment (TME) providing sufficient ingredients for the Fenton reaction necessary for ferroptosis. Upon NIR laser irradiation, the loaded Fe²⁺ is released and a thermal gradient is simultaneously formed owing to the asymmetric PDA coating, thus endowing the nanomotor with self-thermophoresis based enhanced diffusion for subsequent lysosomal escape and tumor penetration. Therefore, the release of ferrous ions (Fe²⁺), self-supplied H₂O₂, and self-thermophoresis of nanomotors with NIR actuation further improve the synergistic CDT/PTT efficacy, showing great potential for active tumor therapy.