Bimetallic nanoreactor mediates cascade amplification of oxidative stress for complementary chemodynamic-immunotherapy of tumor.

As a promising tumor treatment, chemodynamic therapy (CDT) can specifically catalyze HO into the cytotoxic hydroxyl radical (·OH) via Fenton/Fenton-like reaction. However, the limited HO and weakly acidic pH in tumor microenvironment (TME) would severely restrict the therapeutic efficiency of CDT. Here, a weakly acid activated, HO self-supplied, hyaluronic acid (HA)-functionalized Ce/Cu bimetallic nanoreactor (CBPNs@HA) is elaborately designed for complementary chemodynamic-immunotherapy. In this nanoreactor, the component of peroxide group and Ce/Cu bimetals played the role of HO self-supply and synergistic catalytic Fenton-like reaction, respectively. Specifically, CBPNs@HA can sensitively respond to TME (pH 6.8) and rapidly degrade to generate Ce, Cu and HO. The high-valence Ce would be reduced by the intracellular glutathione (GSH) to generate Ce and this process could be accelerated by Cu  via synergistic effect of Ce/Cu. Particularly, the low-valence metallic ions (Ce and Cu) can react with the produced HO to generate a multitude of reactive oxygen species (ROS). These cascaded effects can significantly amplify oxidative stress and seriously disturb the redox balance of tumor cells, inducing the potent immunogenic cell death (ICD) to release tumor-specific antigens and thereby activating the powerful antitumor immune responses. After combined with immune checkpoint blockade (ICB), CBPNs@HA can significantly heighten antitumor effects to inhibit the growth of primary and metastatic tumors, and dramatically prolong the survival lifetime of 4T1 tumor-bearing mice to 60 days. This work provides a materials-based strategy for enhanced CDT and highlights new opportunities for complementary chemodynamic-immunotherapy.