Sequentially Responsive Framework‐Reconstituted Highly‐Active Selenium Nanoparticles Potentiate NK Cell Surveillance against Hepatocellular Carcinoma through Mitochondrial Dysregulation and NKG2DLs‐Upregulation

Abstract Immunotherapy for hepatocellular carcinoma (HCC) remains highly challenges of immunosuppressive tumor microenvironment (TME) that hinders immune cells infiltration, and suppresses immune activation. Targeting natural killer (NK) cells, which is the major immune cells in liver, offers a promising strategy to improve the therapeutic efficacy of HCC through rephasing TME. In this study, frame‐reconstituted selenium (Se) nanoparticles (Se/ZIF8) are developed using a metal–organic framework (zeolitic imidazolate framework‐8, ZIF8) to potentiate NK cell‐mediated HCC immunotherapy. Water‐insoluble Se powder is encapsulated within ZIF8 nanoframeworks, yielding Se/ZIF8 nanomaterials with dual pH and reactive oxygen species (ROS) responsiveness. Se/ZIF8 regulates tumor and NK cells sequentially through concentration and metabolic switching in tumor microenvironment. Initial administration of Se/ZIF8 inhibits mitochondrial respiration of tumor cells, promotes the recognition and infiltration of NK cells in tumors by up‐regulating NKG2DLs on the tumor surface. After tumor uptake and metabolism, subsequent exposure to a reduced Se/ZIF8 concentration mitigates ROS‐induced NK cell damage while promoting NK cell proliferation and activation. This strategic dosing regimen significantly enhances NK cell infiltration, chemotaxis and cytotoxicity in an orthotopic HCC mouse model. Collectively, this study presents a novel nanomedical approach for tumor suppression through improving NK cell activation and infiltration to achieve deep‐penetrating HCC immunotherapy.