Structure-Engineered Lipid–Mineral Nanoparticles for Ligand-Free Myeloid RNAi Delivery in Alzheimer’s Disease

Abstract Peripheral myeloid cells are key regulators of systemic inflammation and promising targets for immune intervention in Alzheimer’s disease (AD). However, selective in vivo small interfering RNA (siRNA) delivery to these cells remains challenging because conventional lipid nanoparticles often exhibit predominant hepatic accumulation and usually require ligand or antibody modification for immune-cell targeting. Here, we report a structure-engineered lipid–mineral nanoparticle platform, termed MCP, for ligand-free myeloid RNA interference (RNAi) delivery. MCP integrates a calcium phosphate mineral phase with a phosphatidic acid-enriched lipid interface, enabling efficient siRNA incorporation. The Ca2+–lipid cooperative architecture promoted macropinocytosis-dependent uptake and preferential siRNA delivery to peripheral myeloid cells in vivo, particularly Ly6Chigh monocytes and macrophages, with enhanced delivery under AD-associated inflammatory conditions. Systemic delivery of MCP carrying siRNA against triggering receptor expressed on myeloid cells 1 (TREM1) attenuated neuroinflammatory and neurodegenerative pathology in an AD mouse model, supporting peripheral myeloid reprogramming as a route to modulate central nervous system (CNS) disease progression. Notably, MCP also achieved efficient TREM1 silencing in AD patient-derived peripheral blood mononuclear cells (PBMCs) and restored TREM1 expression toward healthy-control levels. This work establishes a structure-driven, ligand-free lipid–mineral RNAi platform for peripheral immune intervention in AD.