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Herein, we develop an engineered exosomal siRNA delivery platform for systemic, neuron\u2010targeted 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\u2010derived peptide, the system enables receptor\u2010mediated 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\u2010interacting 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\u2010associated 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\u2010defined, cell\u2010derived biomaterials as a generalizable strategy for overcoming delivery barriers in neurological diseases.<\/jats:p>","DOI":"10.1002\/advs.76558","type":"journal-article","created":{"date-parts":[[2026,7,11]],"date-time":"2026-07-11T22:24:35Z","timestamp":1783808675000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Neuron\u2010Targeted Exosomal Delivery of siRNA Against RIPK3 Slows Neurodegenerative Progression in Alzheimer's Disease"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0009-0000-4820-5126","authenticated-orcid":false,"given":"Chi","family":"Zhang","sequence":"first","affiliation":[{"name":"School of Basic Medical Sciences Harbin Medical University  Harbin Heilongjiang China"},{"name":"The Heilongjiang Provincial Joint Laboratory of Basic 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