Long‐Lasting Reactive Oxygen Species Generation by Porous Redox Mediator‐Potentiated Nanoreactor for Effective Tumor Therapy

Abstract The therapeutic efficiency of reactive oxygen species (ROS)‐based nanotherapeutics is restrained by the rigorous production conditions of relatively sufficient and kinetically matching supply of intracellular substrates. The cumulative disruption of redox homeostasis and consequent pathology (e.g., Parkinson's disease) with low levels of substrates in living organisms may provide a promising model for ROS‐based therapy. Herein, a catechol chemistry‐mediated ternary nanostructure is prepared for long‐lasting generation of oxidative •OH in weakly acidic, low H₂O₂ homeostasis conditions of tumor. This platform employs mesoporous polydopamine (MPDA) as the porous redox mediator, while PDA‐induced sequential precipitation and biomineralization lead to hydroxy iron oxide (FeOOH) as the “iron reservoir,” and calcium phosphate (CaP) as the pH‐sensitive sheddable shell. In weakly acidic conditions, the CaP layer can be degraded to expose the catalytic surface of Fe‐dopamine interplay, where FeOOH dissolution, Fe(III) chelation, Fe(III) reduction, Fe(II) release take place sequentially and continuously for Fe(II) recycling and Fenton catalysis. Both in vitro and in vivo studies verify the significant inhibition of cancer cells and tumor regression, which can also be strengthened by the local photothermal heating. This work establishes the first paradigm of pathologically inspired nanohybrids of ROS generators with long‐lasting efficacy for cancer therapy.