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Single cell multiomic readouts reveal that cellular heterogeneity impacts lipid nanoparticle-mediated mRNA delivery

ABSTRACT: Single cell multiomic readouts reveal that cellular heterogeneity impacts lipid nanoparticle-mediated mRNA delivery

PROVIDER: PRJNA773730 | ENA |

REPOSITORIES: ENA

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Single cell multiomic readouts reveal that cellular heterogeneity impacts lipid nanoparticle-mediated mRNA delivery

Project description:We report the development of a new multiomic nanoparticle delivery system called Single cEll Nanoparticle Transcriptome-sequencing (SENT-seq), which quantifies how dozens of lipid nanoparticles (LNPs) deliver DNA barcodes and mRNA into cells, subsequent protein production, and the transcriptome, with single cell resolution. We show from the sequencing data that cell heterogeneity influences the efficiency with which LNPs deliver mRNA therapies, and identify cell subtypes that exhibit particularly high or low LNP uptake as well as genes associated with those subtypes. These data suggest that cell subsets have distinct responses to LNPs, and that these differential interactions can affect mRNA therapies.

2023-01-23 | GSE186395 | GEO

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Lipid nanoparticle delivery promotes cell-type-specific distribution of antisense oligonucleotides in the brain

Project description:Antisense oligonucleotides (ASOs) are being actively investigated as potential therapeutics for a broad range of neurodegenerative diseases. While these small oligonucleotides have been effective in the clinic, many basic questions regarding ASO internalization, trafficking, and modes of enhancing delivery remain. To address these questions, we investigated how lipid nanoparticle (LNP) delivery affects ASO uptake and distribution in the brain. We show that ASOs are internalized and active in central nervous system (CNS) cell types both in vivo and in vitro. While differential cellular activity and polarization states do not affect ASO potency, encapsulating ASOs in LNPs increases ASO activity up to 100-fold in cultured CNS cells. This dramatic increase in efficacy is facilitated by the intracellular trafficking of ASOs away from lysosomes or enhanced ASO uptake, which is cell-type-specific. We assessed the translatability of these results by screening ASO-LNPs in vitro and intracerebroventricularly injecting top performing formulations in mice. ASO-LNP delivery induced a strong ASO-dependent microgliosis response in the brain revealing that LNP encapsulation cannot mask ASO-mediated toxicity. However, LNP-delivered ASOs did not downregulate mRNA levels in bulk tissue due to changes in ASO distribution. While ASOs distribute widely across the brain after bulk injection, ASO-LNPs are preferentially internalized by cells lining the blood vessels and ventricles. Consistent with our findings in cells, ASOs localize to the endolysosomal system following both ASO and ASO-LNP delivery in the brain as determined using immunoelectron microscopy. These data provide valuable insights into how LNPs regulate ASO uptake and distribution in the brain, and support further development of ASO-LNPs for treating CNS disorders.

2023-05-15 | GSE220777 | GEO

Nanoparticle stereochemistry-dependent endocytosis improves in vivo mRNA delivery

Project description:Nanoparticle stereochemistry-dependent endocytosis improves in vivo mRNA delivery

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Lipid Nanoparticle-Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

Project description:Lipid Nanoparticle-Mediated Delivery of Anti-miR-17 Family Oligonucleotide Suppresses Hepatocellular Carcinoma Growth

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Lipid nanoparticle delivery promotes cell-type-specific distribution of antisense oligonucleotides in the brain

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Therapeutic Delivery of Targeted Nanoparticle Cannabinoid Equivalents

Project description:Nanoparticles and nano delivery systems are continuously being refined and developed as means of treating numerous human diseases by site-specific, and target-oriented delivery of medicines. The nanoparticles can carry therapeutic cargo or be medicinal themselves by virtue of their constitutional structural components. Here we report the ability of synthetic N-acylethanolamides, linoleoylethanolamide (LEA) and oleoylethanolamide (OEA), with endocannabinoid-like activity, to form spherical colloidal nanoparticles that when conjugated with tissue specific homing molecules, can localise to specific areas of the body, and reduce inflammation. The opportunities to mediate pharmacological effects of endocannabinoids at targeted sites provides a novel drug delivery system with increased medicinal potential to treat many diseases in many areas of medicine.

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Project description:Silencing HoxA1 in vivo by intraductal delivery of nanoparticle-formulated siRNA reduced mammary tumor incidence by 75% , reduced cell proliferation, and prevented loss of ER and PR expression. 8 week wild type FVB mouse whole mammary gland and 8week to 20 week transgenic FVB C3(1)-SV40Tag mouse whole mammary gland

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