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.
Reactive oxygen species (ROS) driven endoplasmic reticulum (ER) stress is highly promising for tumor therapy but restrained by the nondurable introduction and limited lifetime of oxidative species. Here, a therapeutic nanosystem with sustainable ROS generation ability was developed by accommodating luminol derivatives (L012) in hyaluronic acid‐modified metal‐organic frameworks of Fe3+ and porphyrin ligand (TCPP). After particle accumulation in the tumor, ∙OH radicals from Fe3+ sites catalyzed conversion of H2O2 can react with confined L012 transducers to generate chemiluminescence (CL). Because of the distance constraints, the CL energy was significantly extracted (96%) by adjacent TCPP and further activate oxygen to long‐lifetime singlet oxygen (1O2), whose yield can be further boosted by the catalase‐like activity of the frameworks. By regulating the substrate consumption through energy conversion, the cascade process resulted in increased ROS levels (2.4‐fold) and sustainable oxidation (24 h), which induced continuously accumulated ER stress, high autophagic levels, and amplified lethality against the tumor. This work opens a new avenue to explore reticular nanostructures with complementarily arranged and synergistically spaced conversion units in advancing ROS therapy.
Cell membrane barrier which dominates the therapeutic efficacy and systemic side effects is a major bottleneck in the field of drug delivery. Herein, a therapeutic system capable of photothermally triggered...
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