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Tumor Microenvironment Triggered Cascade‐Activation Nanoplatform for Synergistic and Precise Treatment of Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) is one of the most common and deadliest malignancy cancers, which remains a major global health problem. At present, over 50% of patients with HCC have implemented systemic therapies, such as interventional therapy or local chemotherapy that are scarcely effective and induce serious side effects to the remaining normal liver, further limiting their clinical outcomes. Herein, a tumor microenvironment triggered cascade‐activation nanoplatform (A‐NPLap/TPZ) is prepared based on β‐lapachone (β‐Lap) and tirapazamine (TPZ) for the synergistic therapy of HCC. The A‐NPLap/TPZ exerts its targeting effect by binding to the receptor of tumor cells with an external aptamer. In the tumor microenvironment, the nanoplatform can realize H2O2‐triggered disassembly to release β‐Lap and TPZ. The released β‐Lap generates ROS to induce tumor cell apoptosis under the catalysis of the tumor cell over‐expressed NAD(P)H‐quinone oxidoreductase‐1 (NQO1) enzyme. In this process, oxygen is consumed to intensify tumor hypoxia, and eventually cascade activates TPZ to exert the anti‐tumor effect. The studies in vitro and in vivo consistently demonstrate that the as‐prepared A‐NPLap/TPZ nanoplatform possesses an excellent synergistic anti‐tumor effect. This design of nanoplatform with cascade activation effect provides a promising strategy for HCC treatment.