Micro-armory Bearing Natural Killer Cells in Hydrogel Enable Durable in Situ Activation and Localized Reinvigoration of Antitumor Cytotoxic Immunity

Natural killer (NK) cells play a pivotal role in innate immunity, effectively eliminating tumor cells. However, their therapeutic potential in solid tumors is limited due to challenges such as limited infiltration, poor persistence, and functional exhaustion. To address this, NK92 cells are empowered with micro-armory (MA) of interleukin 15 (IL15) and subsequently encased in an injectable supramolecular hydrogel based on hydroxypropyl methylcellulose-nanoparticle interactions. The biocompatible hydrogel serves as a locoregional depot for engineered NK92 cells and confers sustained release. Owing to ambient release of IL15, MA backpacking to NK cell surface assists in situ maintenance in cell survival, activation, and cytotoxicity. In a mouse model of subcutaneous 4T1 breast cancer, the biohybrid extends the localized retention of NK92 cells to at least 15 days, enhances tumor infiltration and facilitates localized intra-tumoral distribution of IL15, thereby potently inhibiting tumor growth. In ex vivo model of human breast cancer tissues, engineered NK92 cells demonstrate superior functionality and further re-activate cytotoxic T cells by delivering IL15, consistently augmenting anti-tumor efficacy. The strategy integrating surface-engineered NK cells and localized hydrogel enables persistently in situ cell activation and subsequent intra-tumoral immune reinvigoration, disclosing clinically translational potential for solid tumor therapy.