Acidity-responsive nanocages as robust reactive oxygen species generators with butterfly effects for maximizing oxidative damage and enhancing cancer therapy.

Recently, with the rational design of transition metal-containing nanoagents, chemodynamic therapy (CDT) has been developed and considered a promising method for cancer therapy through Fenton and Fenton-like reaction-induced hydroxyl radical (·OH) generation and cellular oxidative damage. However, it is still a great challenge to realize high reactive oxygen species (ROS) generation and therapeutic efficiency under the strict conditions of the tumor microenvironment (TME). Herein, we design and fabricate a TME-responsive core-shell nanocage composed of a CaCO nanolayer and a heterogeneous CoP core (CaCO@CoP, CCP) with the synergy of CDT and calcium overload to maximize oxidative damage and enhance cancer therapy. The CaCO nanoshell is sensitive to pH and can be rapidly degraded upon endocytosis, leading to intracellular Ca accumulation, which further triggers the production of mitochondrial ROS. Subsequently, the CoP hollow nanocage with fully exposed Co active sites has high Fenton-like reactive activity to produce ·OH and induce mitochondrial damage. Mitochondrial damage and ROS elevation, in turn, can modulate Ca dynamics and augment calcium overload. The reciprocal interaction and loop feedback between calcium overload and photoenhanced ROS generation via photothermal therapy (PTT) can further trigger the immunogenic cell death (ICD) process to activate the maturation of dendritic cells (DCs), activation of cytotoxic and helper T cells, and excretion of proinflammatory cytokines to enhance antitumor immunity in vivo. With the butterfly effect, CCP finally brings forth a greatly enhanced cancer therapeutic outcome in murine models.