An AIM2 inflammasome biomimetic mineralization inhibitor for vascular dementia therapy

<b>Rationale:</b> Absent in melanoma 2 (AIM2) inflammasome-mediated effector plays critical roles in multiple disease pathologies. While nanotechnology has revolutionized therapeutic development through novel approaches, the potential regulatory effects of nanoparticles on AIM2 inflammasome activity remain unexplored. Here, guided by clinical patient data and computational modeling, we developed an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for vascular dementia (VaD) therapy. <b>Methods:</b> GEO datasets were analyzed to compare AIM2 inflammasome component expression in VaD patient brains versus controls. Molecular dynamics simulations identified high-affinity binding between manganese ferrocyanide and the AIM2 protein. We synthesized hollow manganese Prussian blue nanoparticles (HMPB) via biomineralization and functionalized them with M2 macrophage-derived extracellular vesicles (M2exo@HMPB). Therapeutic efficacy was evaluated in a VaD rat model through intravenous and intracerebroventricular administration, employing behavioral assessments, histopathological analysis, and inflammatory cytokine profiling. AIM2 inflammasome assembly and pyroptosis were investigated through protein immunoblotting, scanning electron microscopy/transmission electron microscopy (SEM/TEM) imaging of microglial cells, and primary microglia cultures under hypoxic-hypoglycemic conditions. <b>Results:</b> Gene expression analysis demonstrated significantly elevated levels of AIM2 inflammasome components in VaD patients compared to normal controls. Molecular dynamics simulations revealed effective binding of manganese ferrocyanide to AIM2. M2exo@HMPB targeted central inflamed sites and were ultimately phagocytosed by microglia. In an <i>in vitro</i> sustained hypoxic-hypoglycemic model, M2exo@HMPB inhibited AIM2 inflammasome assembly and pyroptosis in primary microglia, thereby reducing IL-18/IL-1β release and promoting neuronal survival. In VaD rat models, M2exo@HMPB alleviated neuronal loss and white matter lesions while improving learning and executive functions. Additionally, M2exo@HMPB demonstrated favorable <i>in vivo</i> biosafety. <b>Conclusions</b>: Integrating clinical bioinformatics with computational drug design, this study establishes a translational paradigm for nanomaterial development. M2exo@HMPB serves not only as an AIM2 inflammasome-targeting biomimetic mineralization inhibitor for VaD therapy but also provides new insights for treating AIM2-mediated cell death pathologies.