Tumor Microenvironment-Responsive CA@ZIF-8/MnO 2 Nanoreactor for Self-Reinforcing Cascade Chemodynamic Therapy and Immunomodulation

Chemodynamic therapy (CDT), which utilizes endogenous hydrogen peroxide (H ₂ O ₂ ) to generate hydroxyl radicals ( ^• OH) via Fenton-like reactions, faces critical limitations in clinical translation, including insufficient intratumoral H ₂ O ₂ levels and glutathione (GSH)-mediated ROS scavenging. To address these challenges, we developed a tumor microenvironment (TME)-responsive nanoreactor, CA@ZIF-8/MnO ₂ (CZM), integrating dual functionalities of GSH-depleting and H ₂ O ₂ self-supplying for cascade-amplified CDT. The ZIF-8 framework serves as a biodegradable carrier for chlorogenic acid (CA), which converts superoxide (O ₂ ^•− ) into H ₂ O ₂ , while the MnO ₂ shell depletes GSH to yield Mn ²⁺ , a Fenton-like catalyst. Upon internalization by tumor cells, the MnO ₂ shell reacts with GSH to produce Mn ²⁺ , which catalyzes the conversion of H ₂ O ₂ to ^• OH, while simultaneously depleting GSH to enhance CDT efficacy. Additionally, the acidic TME triggers the release of CA, which elevates H ₂ O ₂ levels through its self-oxidation property, creating a self-reinforcing cycle. In vitro and in vivo studies demonstrated that CZM NPs not only enhance ^• OH generation but also trigger immunogenic cell death (ICD), promoting antitumor immune responses. Furthermore, CZM NPs promote the polarization of tumor-associated macrophages towards the M1 antitumor phenotype, reshaping the immunosuppressive TME. RNA-seq and pathway analysis further revealed that CZM NPs modulate key signaling pathways, including NF-κB, to induce apoptosis and enhance antitumor immunity. Overall, these findings highlight the potential of CZM NPs as a multifunctional nanoplatform for cascade-amplified CDT and immunotherapy.