Nanoparticle‐Mediated Delivery of Anti‐PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation
Name
Advanced Materials - 2023 - Ralvenius - Nanoparticle‐Mediated Delivery of Anti‐PU 1 siRNA via Localized Intracisternal.pdf
Description
Published version
Size
3.86 MB
Format
Adobe PDF
Checksum (MD5)
93d7a19473a6e3c2083737d9a37ca0c7
Author(s)
Ralvenius, William T
Andresen, Jason L
Huston, Margaret M
Penney, Jay
Bonner, Julia Maeve
Fenton, Owen S
Langer, Robert
Tsai, Li‐Huei
Date Issued
February 22, 2024
Journal
Advanced Materials
Publisher
Wiley
Citation
W. T. Ralvenius, J. L. Andresen, M. M. Huston, J. Penney, J. M. Bonner, O. S. Fenton, R. Langer, L.-H. Tsai, Nanoparticle-Mediated Delivery of Anti-PU.1 siRNA via Localized Intracisternal Administration Reduces Neuroinflammation. Adv. Mater. 2024, 36, 2309225.
Version
Final published version
Abstract
Neuroinflammation is a hallmark of neurodegenerative disorders including Alzheimer's disease (AD). Microglia, the brain's immune cells, express many of the AD‐risk loci identified in genome wide association studies and present a promising target for anti‐inflammatory RNA therapeutics but are difficult to transfect with current methods. Here, several lipid nanoparticle (LNP) formulations are examined, and a lead candidate that supports efficient RNA delivery in cultures of human stem cell‐derived microglia‐like cells (iMGLs) and animal models of neuroinflammation is identified. The lead microglia LNP (MG‐LNP) formulation shows minimal toxicity and improves delivery efficiency to inflammatory iMGLs, suggesting a preference for delivery into activated microglia. Intraperitoneal injection of the MG‐LNP formulation generates widespread expression of the delivered reporter construct in all organs, whereas local intracisternal injection directly into the cerebrospinal fluid leads to preferential expression in the brain. It is shown that LNP‐mediated delivery of siRNA targeting the PU.1 transcription factor, a known AD‐risk locus, successfully reduces PU.1 levels in iMGLs and reduces neuroinflammation in mice injected with LPS and in CK‐p25 mice that mimic the chronic neuroinflammation seen in AD patients. The LNP formulation represents an effective RNA delivery vehicle when applied intrathecally and can be broadly utilized to test potential neuroinflammation‐directed gene therapies.
MIT Department
Picower Institute for Learning and Memory
Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences
Massachusetts Institute of Technology. Department of Chemistry
Massachusetts Institute of Technology. Department of Chemical Engineering
Broad Institute of MIT and Harvard
Terms of Use
Creative Commons Attribution-Noncommercial
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DOI of Published Version
https://doi.org/10.1002/adma.202309225
