Biomimetic virus-like mesoporous silica nanoparticles activate NK cells indirectly via monocyte crosstalk

Cancer immunotherapies show clinical promise but often rely on T-cell priming and are limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Innate immune activation offers a complementary strategy, with specific aim in natural killer (NK) cell activation for antigen-independent response. Biomimetic nanoparticles combining virus-like morphology with cell membrane (CM) coating offer a strategy to engage this innate immune axis. This study investigates virus-like mesoporous silica nanoparticles (VLPSi) with tunable spikes, surface functionalization, and CM coating as innate immunity modulators. Optimization revealed that longer spikes, amine functionalization, and CM coating synergistically enhance NK cell activation within human PBMCs, as indicated by CD69/CD25 upregulation and IFN-γ secretion. CD14 ⁺ monocyte depletion attenuated activation, identifying monocyte-dependent crosstalk as a key mechanism. In purified NK cells, engineered CM-coated VLPSi induced early activation and supported feeder-free expansion. These results define topology, surface chemistry, and CM coating as parameters for innate immune modulation.