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Lipid nanoparticles for antisense oligonucleotide gene interference into brain border-associated macrophages
Macarena Calero1,2, Lara H Moleiro1,3, Aline Sayd2,4,5
1Department of Physical Chemistry, Faculty of Chemistry, Complutense University, Madrid, Spain.
Frontiers in Molecular Biosciences
|November 21, 2022
Summary
Researchers developed novel lipid nanoparticles (LNPs) carrying DNA antisense oligonucleotides (ASOs) to target brain macrophages. This therapy aims to silence genes involved in neuroinflammation, offering a new approach for CNS disorders.
Area of Science:
- Neuroscience
- Nanotechnology
- Gene Therapy
Background:
- Neuroinflammation is implicated in neuropsychiatric disorders like depression and schizophrenia.
- Lipocalin-type prostaglandin D synthase (L-PGDS) is an anti-inflammatory enzyme in brain macrophages, with altered expression in these conditions.
- Targeting specific gene expression in brain macrophages offers a potential therapeutic strategy for CNS diseases.
Purpose of the Study:
- To develop and evaluate lipid nanoparticles (LNPs) encapsulating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for targeted gene silencing in brain border-associated macrophages (BAMs).
- To inhibit the expression of the L-PGDS gene, a key target in neuroinflammation.
- To establish a novel central nervous system (CNS) gene therapy platform for neuroinflammation-related pathologies.
Main Methods:
- Colloidal synthesis using the Bligh-Dyer emulsion inversion method to formulate GR@LNPs.
- Functionalization of LNPs with a mannosylated lipid for selective targeting of BAMs via mannose receptors.
- Characterization of GR@LNPs using light scattering, zeta potential, and transmission electron microscopy.
- In vivo evaluation of gene interference in Wistar rats after intracerebroventricular (ICV) injection.
Main Results:
- GR@LNPs demonstrated high GR packing density and a compact multilamellar structure.
- Mannosylated GR@LNPs were selectively phagocytosed by BAMs.
- In vivo gene interference targeting L-PGDS was detected in rats after ICV delivery.
- The developed nanovectors showed bio-orthogonal activity, specifically targeting L-PGDS transcripts.
Conclusions:
- The study presents a proof-of-concept for ASO-loaded LNPs as a targeted gene therapy for neuroinflammation.
- Mannose-functionalized LNPs enable selective delivery to BAMs in the CNS.
- This approach holds promise for developing advanced therapies for neuropsychiatric disorders by modulating neuroinflammation at the genetic level.
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