Abstract

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 catechol-rich 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.