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The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory

ABSTRACT: The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory

PROVIDER: PRJNA704856 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR13783173_1.fastq.gz	Fastqsanger.gz
	SRR13783173_2.fastq.gz	Fastqsanger.gz
	SRR13783174_1.fastq.gz	Fastqsanger.gz
	SRR13783174_2.fastq.gz	Fastqsanger.gz
	SRR13783175_1.fastq.gz	Fastqsanger.gz

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The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory

Project description:Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against coronavirus disease in 2019 (COVID-19). Clinical trials and ongoing vaccinations present with very high protection levels with varying degrees of side effects. However, the nature of the reported side effects remains poorly defined. Here we present evidence that LNPs used in many preclinical studies are highly inflammatory in mice. Intradermal injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate. In summary, here we show that the LNPs used for many preclinical studies are highly inflammatory. Thus, their potent adjuvant activity and reported superiority comparing to other adjuvants in supporting the induction of adaptive immune responses could stem from their inflammatory nature. Furthermore, the preclinical LNPs are similar to the ones used for human vaccines, which could also explain the observed side effects in humans using this platform.

2021-03-16 | GSE167521 | GEO

The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory.

Project description:Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against COVID-19. Clinical trials and ongoing vaccinations present with varying degrees of protection levels and side effects. However, the drivers of the reported side effects remain poorly defined. Here we present evidence that Acuitas' LNPs used in preclinical nucleoside-modified mRNA vaccine studies are highly inflammatory in mice. Intradermal and intramuscular injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate, with mechanism unresolved. Thus, the mRNA-LNP platforms' potency in supporting the induction of adaptive immune responses and the observed side effects may stem from the LNPs' highly inflammatory nature.

| S-EPMC8604799 | biostudies-literature

The mRNA-LNP platform's lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory.

Project description:Vaccines based on mRNA-containing lipid nanoparticles (LNPs) are a promising new platform used by two leading vaccines against coronavirus disease in 2019 (COVID-19). Clinical trials and ongoing vaccinations present with very high protection levels and varying degrees of side effects. However, the nature of the reported side effects remains poorly defined. Here we present evidence that LNPs used in many preclinical studies are highly inflammatory in mice. Intradermal injection of these LNPs led to rapid and robust inflammatory responses, characterized by massive neutrophil infiltration, activation of diverse inflammatory pathways, and production of various inflammatory cytokines and chemokines. The same dose of LNP delivered intranasally led to similar inflammatory responses in the lung and resulted in a high mortality rate. In summary, here we show that the LNPs used for many preclinical studies are highly inflammatory. Thus, their potent adjuvant activity and reported superiority comparing to other adjuvants in supporting the induction of adaptive immune responses likely stem from their inflammatory nature. Furthermore, the preclinical LNPs are similar to the ones used for human vaccines, which could also explain the observed side effects in humans using this platform.

| S-EPMC7941620 | biostudies-literature

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

Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function. VLDLHDL corona

Project description:The MS data set contains the result from HDL VLDL corona used in the publication, titled Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function.

2023-06-07 | PXD041944 | Pride

Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function. Rat Plasma

Project description:The MS data set contains the result from each individual rat plasma used in the publication, titled Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function.

2023-06-07 | PXD041925 | Pride

Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function. Individual corona

Project description:The MS data set contains the result from each individual rat plasma derived corona used in the publication, titled Multiomics analysis of naturally efficacious LNP coronas reveals high-density lipoprotein is necessary for LNP function.

2023-06-07 | PXD041938 | Pride

Total RNA expression in extracellular vesicles (EVs) derived from untreated and lipid nanoparticle(LNP) treated cells: lung epithelial, umbilical vein endothelial, and cardiac progenitor cells

Project description:The study used next-generation sequencing to compare mRNA content of EVs from 3 different cell origins which are untreated control or treated with LNP containing VEGFA mRNA. Our goal is to carry out functional and pathway analysis of the differentially expressed genes. The RNA profiles of EV content from treated and untreated cells; lung epithelial (HTB-177) , umbilical vein endothelial (HUVEC), and cardiac progenitor cells(CPC), were generated by RNA-Seq using Illumina NovaSeq6000. Differentially expressed genes were identified using the DESeq2 package. We found that the VEGFA mRNA was among the most upregulated genes in EVs from LNP treated cells. We also identified multiple genes and pathways associated with angiogenesis and cardiac conditions that were activated in the EVs derived from treated cells. The result suggests that VEGFA-LNP were processed by the cells and certain portions of the mRNA were packaged into EVs and released into the cell culture medium.

2023-05-03 | GSE198486 | GEO

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

Custom-designed lipid-based nanoparticles efficiently deliver mRNA to reverse the pathogenesis of LAL deficiency in a preclinical model

Project description:Lysosomal acid lipase (LAL) is a crucial enzyme responsible for the hydrolysis of triglycerides (TGs) and cholesteryl esters (CEs) in the lysosomes. LAL deficiency results in the extensive storage of CEs and TGs in the liver and the spleen, inducing hepatosplenomegaly, and can be a life-threatening condition with patients rarely surviving beyond 6 months of age in the most aggressive form. Using messenger ribonucleic acid (mRNA) for protein replacement is an innovative approach to treating LAL deficiency. Here, we describe the development of a new lipid-based nanoparticle (LNP) formulation capable of efficiently delivering LAL mRNA and restoring LAL activity in affected organs mediating significant reversal of the pathological progression in a highly predictive preclinical model. A combinatorial library of mRNA-LNPs was generated and screened both in vitro and in vivo to yield a new formulation with a higher potency than an FDA-approved MC3-based nano-formulation. In vivo evaluation revealed that the new formulation could promote a more sustained and superior LAL expression. Multiple injection regimen was able to mitigate hepatosplenomegaly and reduce the lipid accumulation of CEs and TGs by 20-30% in the liver and 50% in the spleen. Furthermore, liver inflammation processes and development of fibrosis were significantly diminished. These findings provide strong evidence that mRNA-LNP is a very promising approach for the chronic treatment of LAL deficiency and support the clinical translation of mRNA therapy to overcome side effects and challenges encountered with traditional enzyme replacement therapies.

2024-12-06 | GSE280933 | GEO

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