The mRNA-LNP platform’s lipid nanoparticle component used in preclinical vaccine studies is highly inflammatory
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ABSTRACT:
PROVIDER: PRJNA704856 | ENA |
REPOSITORIES: ENA
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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
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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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| S-EPMC7116839 | biostudies-literature
Project description:Analysis of the role of the proteome on lipid nanoparticle distribution
2023-03-16 | PXD032311 | Pride
Project description:Background: Despite advances in therapeutics, outcomes for hepatocellular carcinoma (HCC) remain poor and there is an urgent need for efficacious systemic therapy. Unfortunately, drugs that are successful in preclinical studies often fail in the clinical setting, and we hypothesize that this is due to functional differences between primary tumors and commonly used preclinical models. In this study, we attempt to answer this question by comparing tumor morphology and gene expression profiles between primary tumors, xenografts and HCC cell lines. Methods: Hep G2 cell lines and tumor cells from patient tumor explants were subcutaneously (ectopically) injected into the flank and orthotopically into liver parenchyma of Mus Musculus SCID mice. The mice were euthanized after two weeks. RNA was extracted from the tumors, and gene expression profiling was performed using the Gene Chip Human Genome U133 Plus 2.0. Principal component analyses (PCA) and construction of dendrograms were conducted using Partek genomics suite. Results: PCA showed that the commonly used HepG2 cell line model and its xenograft counterparts were vastly different from all fresh, primary tumors. Expression profiles of primary tumors were also significantly divergent from their counterpart patient-derived xenograft (PDX) models, regardless of the site of implantation. Xenografts from the same primary tumors were more likely to cluster together regardless of site of implantation, although heat maps showed distinct differences in gene expression profiles between orthotopic and ectopic models. Conclusions: The data presented here challenges the utility of routinely used preclinical models. Models using HepG2 were vastly different from primary tumors and PDXs, suggesting that this is not clinically representative. Surprisingly, site of implantation (orthotopic versus ectopic) resulted in limited impact on gene expression profiles, and in both scenarios xenografts differed significantly from the original primary tumors, challenging the long-held notion that orthotopic PDX model is the gold standard preclinical model for HCC.
2015-11-17 | GSE72981 | GEO
Project description:We sequenced the transcroptome of isolated nanoparticle positive and nanoparticle negative tumour endothelial cells from mouse 4T1 mammary tumours
2021-09-07 | GSE172496 | GEO
Project description:Laboratory mice comprise an inexpensive and expeditious model organism for preclinical vaccine testing; however, vaccine immunogenicity often fails to adequately translate to humans. Recent reports indicate that reconstituting physiologic microbial experience to specific pathogen free (SPF) mice induces durable immunological changes that better recapitulate the human immune system. We examined the impact of microbial experience on responses to vaccination after cohousing laboratory mice with pet store mice. We demonstrate that human transcriptional responses to influenza vaccination are better recapitulated in cohoused mice. Induction of humoral responses by vaccination was dampened in cohoused mice and resulted in poor control upon challenge. Additionally, the establishment of protective heterosubtypic T cell immunity was compromised in cohoused mice. In summary, SPF mice exaggerated both humoral and T cell protection induced by influenza vaccines compared to cohoused mice, suggesting that reconstituting microbial experience in laboratory mice through cohousing may better inform preclinical vaccine testing.
2021-10-23 | GSE182858 | GEO
Project description:An antivirulence approach targets bacterial virulence rather than cell viability in the antibiotic approach that can readily lead to drug resistance. Opportunistic human pathogen Pseudomonas aeruginosa produces a variety of virulence factors, and biofilm cells of this bacterium are much more resistant to antibiotics than planktonic cells. To identify novel inorganic antivirulence compounds, the dual screenings of thirty-six metal ions were performed to identify that zinc ions and ZnO nanoparticle inhibited the pyocyanin production and biofilm formation in P. aeruginosa without affecting the growth of planktonic cells. Moreover, zinc ion and ZnO nanoparticle markedly reduced the production of 2-heptyl-3-hydroxy-4(1H)-quinolone and siderophore pyochelin, while increased the production of another sideropore pyoverdine and swarming motility. Further, zinc ion and ZnO nanoparticle clearly suppressed hemolytic activity in P. aeruginosa. Transcriptome analyses showed that ZnO nanoparticle induced zinc cation efflux pump czc operon, porin genes (oprD and opdT), and Pseudomonas type III repressor A ptrA, while repressed pyocyanin-related phz operon, which partially explains the phenotypic changes. Overall, ZnO nanoparticle is a potential candidate for use in an antivirulence approach against persistent P. aeruginosa infection. P. aeruginosa Genechip Genome Array (Affymetrix, P/N 900339) was used in order to study the cells after the addition of ZnO nanoparticles. DNA microarray analysis with one biological replicate was performed with an Affymetrix system. P. aeruginosa was inoculated in 25 ml of LB medium in 250 ml shaker flasks with overnight cultures (1 : 100 dilution). Cells were cultured for 5 h with shaking at 250 rpm with and without ZnO nanoparticles (1 mM). Before sample collection, RNase inhibitor (RNAlater, Ambion, TX, USA) was added, and the cells were immediately chilled with dry ice and 95% ethanol (to prevent RNA degradation) for 30 s before centrifugation at 16,000 g for 2 min. The cell pellets were immediately frozen with dry ice and stored at –80°C. Total RNA was isolated using a Qiagen RNeasy mini Kit (Valencia, CA, USA).
2015-05-25 | E-GEOD-46947 | biostudies-arrayexpress