Engineering mRNA-LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases

Messenger RNA (mRNA) therapeutics delivered by lipid nanoparticles (LNPs) have advanced from concept to clinic at unprecedented speed, yet their promise for neurodegenerative diseases remains largely untapped. Currently intractable age-related 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-brain barrier (BBB), evade innate immune surveillance, and achieve cell-selective expression in the ageing brain. We highlight emerging chemistries, including BBB-shuttling ionizable lipids, peptide-functionalized shells, and liver-detargeted formulations that enable systemic or minimally invasive delivery to the central nervous system (CNS) in animal models. Although no CNS-directed mRNA-LNP has yet reached clinical trials, first-in-human studies for rare metabolic disorders demonstrate favourable safety, manufacturability, and durable protein replacement. Drawing lessons from COVID-19 mRNA vaccines and ongoing liver-targeted 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-dose immunogenicity, and large-scale synthesis of next-generation lipids. Finally, we propose design rules and analytical standards to address outstanding knowledge gaps in expression durability and age-related BBB alterations. Together, these insights chart a path for engineering mRNA-LNP therapeutics capable of meeting the rising burden of neurodegenerative diseases in an ageing global population.