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

Abstract

As a promising tumor treatment, chemodynamic therapy (CDT) can specifically catalyze H₂O₂ into the cytotoxic hydroxyl radical (·OH) via Fenton/Fenton-like reaction. However, the limited H₂O₂ and weakly acidic pH in tumor microenvironment (TME) would severely restrict the therapeutic efficiency of CDT. Here, a weakly acid activated, H₂O₂ 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 H₂O₂ 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 Ce⁴⁺, Cu⁺ and H₂O₂. The high-valence Ce⁴⁺ would be reduced by the intracellular glutathione (GSH) to generate Ce³⁺ and this process could be accelerated by Cu ⁺ via synergistic effect of Ce⁴⁺/Cu⁺. Particularly, the low-valence metallic ions (Ce³⁺ and Cu⁺) can react with the produced H₂O₂ 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.