A dual-transformable MgGa-MOF nanoplatform for HCC therapy via lactate metabolism blockade and immune reactivation

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Abstract
Microwave ablation (MWA) has emerged as one of the preferred modalities for treating hepatocellular carcinoma (HCC). However, its therapeutic efficiency is restricted by lactate accumulation after MWA. Lactate serves as a metabolic fuel for residual tumor cells, as well as acidifies the tumor microenvironment (TME) and impairs immune function, thereby fostering tumor recurrence and metastatic dissemination. Herein, we designed a dual-transformation strategy that turns metabolic fuel into metabolic burden and immunosuppressive pressure into power, implemented via bimetallic MOF-based nanoplatform (Dis@MgGa-MOF@TD/FA, DMGTF NCs), to counteract microwave-induced lactate elevation, reactivate immune activity and suppress primary tumor growth and metastatic progression. Specifically, after intravenous administration, folic acid (FA)-modified DMGTF accumulates in HCC, where microwave irradiation opens the 1-Tetradecanol (TD) gate to release diclofenac sodium (Dis). The released Dis suppresses MCT4-mediated lactate efflux, thereby disrupting lactate-driven energy supply and reshaping the TME. Meanwhile, microwave-activated DMGTF generates abundant ROS to impair mitochondrial lactate oxidation, thereby promoting intracellular lactate accumulation and inducing metabolic stress. Moreover, framework-derived Mg²⁺ restarts T cells, boosts proliferation, and augments IFN-γ secretion, converting immunosuppressive "pressure" into antitumor "power". As a result, DMGTF NCs combined with MW achieve excellent therapeutic effects in a model of hepatocellular carcinoma and lung metastasis. This MOF-based dual-transformation strategy provides a promising solution to the long-standing challenge of post-MWA tumor relapse and dissemination, offering new insights into the effective control of liver cancer.
Funding Information
  • Fundamental Research Program of Shanxi Province (202403021221305)
  • the Science and Education Cultivation Fund of the National Cancer and Regional Medical center of Shanxi Provincial Cancer hospital (QH2023013)
  • the Science and Education Cultivation Fund of the National Cancer and Regional Medical center of Shanxi Provincial Cancer hospital (TD2023003, BD2023004)
  • National Natural Science Foundation of China (82172048, U21A20378)
  • The Science and Technology Cooperation and Exchange Special Project of Shanxi Province (202304041101030)

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