Neuron-Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease.

A major challenge in RNA therapeutics for central nervous system disorders is the lack of delivery systems capable of crossing the blood-brain barrier (BBB) while achieving cell-type-specific targeting. Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron-targeted RNA transport to the brain. The platform leverages exosomes derived from an immortalized mouse hippocampal neuronal cell line as a biomimetic and functionally privileged material source, enhancing neuronal uptake and intracellular delivery efficiency. Through surface functionalization with a rabies virus glycoprotein-derived peptide, the system enables receptor-mediated BBB transcytosis and programmable siRNA loading. In human cortical organoids, the platform achieves efficient cytosolic delivery and robust gene silencing in neurons, demonstrating high delivery precision and bioavailability. As a proof of concept, targeting receptor-interacting protein kinase 3 (RIPK3) modulates necroptosis, a key pathway in inflammatory neurodegeneration. In transgenic mouse models, systemic administration suppresses RIPK3/MLKL signaling, reduces neuronal loss, and alleviates neuroinflammation and tau-associated pathology. Transcriptomic analyses further indicate stabilization of neuronal homeostasis across vulnerable brain regions. Collectively, the study establishes a modular and programmable exosomal RNA delivery platform and highlights age-defined, cell-derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.