Engineering mRNA‐LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases
- 1The Florey Institute of Neuroscience and Mental Health Parkville Victoria Australia
- 2The Florey Department of Neuroscience and Mental Health University of Melbourne Parkville Victoria Australia
- 3Zitra Medicines Pty Ltd, Carlton Victoria Australia
Abstract
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.
Related
- Cuproptosis: New Mechanisms Linking Endothelial Dysfunction to Neurodegenerative Diseases and Therapeutic Prospects
- Psychobiotics and Trace Elements in Neurodegenerative Diseases: From Independent Modulators to Potential Interactions Within the Microbiota–Gut–Brain Axis—Narrative Review
- Carbon Capture and Utilization Through Microalgae and Carbonic Anhydrases: Opportunities, Challenges and Future Directions
- Epigenetic Mechanisms in Neurodegenerative Diseases: From Genetic Regulation to Therapeutic Potential
- Research Progress of Insulin-like Growth Factor-1 in Major Neurodegenerative Diseases
BibTeX
@article{belaidi2026engineering,
title = {{Engineering mRNA‐LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases}},
author = {Abdel Ali Belaidi and Denzil L. Furtado and Francesca Alves and Rebecca M. Nisbet and Scott Ayton and Ashley I. Bush},
journal = {Exploration},
year = {2026},
month = sep,
doi = {10.1002/exp2.70223},
url = {https://doi.org/10.1002/exp2.70223},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Engineering mRNA‐LNP Medicines for the Ageing Brain: Opportunities and Challenges for Neurodegenerative Diseases
AU - Abdel Ali Belaidi
AU - Denzil L. Furtado
AU - Francesca Alves
AU - Rebecca M. Nisbet
AU - Scott Ayton
AU - Ashley I. Bush
PY - 2026
DA - 2026/09/08
JO - Exploration
DO - 10.1002/exp2.70223
UR - https://doi.org/10.1002/exp2.70223
AB - 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.
SN - 2766-8509
SN - 2766-2098
ER -