Natural Killer Cell‐Mimicking Hypoxia‐Responsive Nanomedicines for Tumor‐Specific Suppression and Immune Regulation

Abstract Natural killer (NK) cells, as critical effectors of the innate immune system, can directly recognize and kill tumor cells without prior antigen priming. However, NK cell activity is hindered by hypoxia and immunosuppressive factors in the tumor microenvironment. Herein, NK cell membrane (NKCM)‐camouflaged hypoxia‐responsive nanoparticles (HSF@NK) are developed to co‐deliver ferrocene (Fc) and carbonic anhydrase IX (CAIX) siRNA for an NK cell‐mimicking anticancer strategy, enhancing tumor‐specific cytotoxicity and reversing the immunosuppressive tumor microenvironment. HSF@NK achieves tumor targeting and immune evasion by retaining NKCM proteins. Hypoxic tumor microenvironment triggers the release of Fc and CAIX siRNA, decreasing the intracellular pH by downregulating CAIX to accelerate Fc‐involved Fenton reaction, and amplifies oxidative damage in tumor cells, while remaining non‐cytotoxic to normal cells in vitro. The resulting oxidative stress elicited immunogenic cell death, dendritic cells maturation, and cytotoxic T lymphocyte infiltration, while NKCM proteins promoted M1 macrophage polarization. HSF@NK significantly inhibited tumor growth (≈85.0%) in B16F10 murine tumor models. When combined with anti‐PD‐L1, HSF@NK further enhanced tumor suppression (≈92.4%) and established long‐term immunity in 4T1 tumor models. This approach offers a paradigm shift in the design of NK cell‐inspired nanomedicines and paves the way for reliable strategies for solid tumor therapy.