Despite the accuracy advantages of photothermal therapy (PTT), heat stress‐initiated free radicals and damage‐activated immune cells form a malignant positive feedback cycle following light irradiation. Herein, a 2D allomelanin nanomodulator with perpendicularly oriented oligomer planes is prepared by the guidance of DNA to achieve timely scavenging of reactive oxygen species (ROS) for inflammation and prognosis control following PTT. A large exposure degree of phenol groups and the effective transfer of delocalized electrons result in ultra‐fast redox reactions that can be boosted by a self‐amplifying process through structure disintegration. Compared with conventional photothermal agents, the nanodisks reduce the accumulation of ROS during PTT by 25‐fold, downregulate the proinflammatory factors, and adjust inflammation levels to baseline. Thereby, successful modulation of M2‐type macrophages in paratumor tissues significantly prevents burn wound progression and accelerates tissue repair, while well‐controlled neutrophil extracellular traps and largely recruited CD4+/CD8+ T cells (1.6–3.2‐fold) in the ablation site suppress the relapse of distant tumors. The study provides a useful inspiration on rationally modulating redox active nanostructures to address prognosis issues following PTT.
The elevation of antioxidant defense systems by adaptation response to localized reactive oxygen species (ROS) accumulation may confer resistance to excessive oxidative stress and cause therapeutic lethality. Herein, a highly effective tumor therapy is developed through perturbation in cellular redox homeostasis. Specifically, metal-ion-assisted oxidation polymerization of the melanin precursor (L-DOPA) whose carboxyl groups exert a charge-shielding effect leads to the formation of catecholrich but quinone-deficient nanoparticles (NPs). These NPs possess appreciable ROS-scavenging ability, and particularly the raised quinone group levels in oxidized products can then trigger subsequent depletion of antioxidative species (GSH) and, in turn, the redox-cycle consumption of catechol/quinone groups. After incubating with cells, varying degrees of redox-state and energy metabolism fluctuations with time (∼6 h) are observed, where ROS/GSH levels rebound to a maximum peak (up to ∼280%) higher than the normal redox state after hitting the bottom within a short time (1 h). Notably, systematically triggered redox stress response can sensitize cells to an extremely endangered metastable state. The synergy of temporally photoactivated thermal stress can produce overwhelming oxidative stress, thus leading to significant inhibition of cancer cells. This work established a new paradigm of redox perturbator-based programed and combined cancer therapy.
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