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

ABSTRACT 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.