Tumor microenvironment-responsive CA@ZIF-8/MnO nanoreactor for self-reinforcing cascade chemodynamic therapy and immunomodulation.

Chemodynamic therapy (CDT), which utilizes endogenous hydrogen peroxide (HO) to generate hydroxyl radicals (OH) via Fenton-like reactions, faces critical limitations in clinical translation, including insufficient intratumoral HO levels and glutathione (GSH)-mediated ROS scavenging. To address these challenges, we developed a tumor microenvironment (TME)-responsive nanoreactor, CA@ZIF-8/MnO (CZM), integrating dual functionalities of GSH-depleting and HO self-supplying for cascade-amplified CDT. The ZIF-8 framework serves as a biodegradable carrier for chlorogenic acid (CA), which converts superoxide (O) into HO, while the MnO shell depletes GSH to yield Mn, a Fenton-like catalyst. Upon internalization by tumor cells, the MnO shell reacts with GSH to produce Mn, which catalyzes the conversion of HO to OH, while simultaneously depleting GSH to enhance CDT efficacy. Additionally, the acidic TME triggers the release of CA, which elevates HO 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.