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Currently intractable age\u2010related proteinopathies such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis demand new therapies that combine molecular precision with scalable manufacturing. This review surveys recent advances in engineering LNPs that traverse the blood\u2013brain barrier (BBB), evade innate immune surveillance, and achieve cell\u2010selective expression in the ageing brain. We highlight emerging chemistries, including BBB\u2010shuttling ionizable lipids, peptide\u2010functionalized shells, and liver\u2010detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS\u2010directed mRNA\u2010LNP has yet reached clinical trials, first\u2010in\u2010human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID\u201019 mRNA vaccines and ongoing liver\u2010targeted programmes, we outline a translational roadmap for brain applications. Major hurdles that are critically assessed include efficient endosomal escape in aged neurons, heterogeneity of the senescent BBB, chronic\u2010dose immunogenicity, and large\u2010scale synthesis of next\u2010generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age\u2010related BBB alterations. Together, these insights chart a path for engineering mRNA\u2010LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.<\/jats:p>","DOI":"10.1002\/exp2.70223","type":"journal-article","created":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T08:50:52Z","timestamp":1788857452000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Engineering mRNA\u2010LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases"],"prefix":"10.1002","author":[{"given":"Abdel Ali","family":"Belaidi","sequence":"first","affiliation":[{"name":"The Florey Institute of Neuroscience and Mental Health  Parkville Victoria Australia"},{"name":"The Florey Department of Neuroscience and Mental Health University of Melbourne  Parkville Victoria Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Denzil 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