Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069234 | ENA |
REPOSITORIES: ENA
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Project description:Lipid nanoparticles (LNPs) play a crucial role in addressing genetic disorders, and cancer, and combating pandemics such as COVID-19 and its variants. Yet, in contrast remarkable achievements in siRNA and mRNA delivery, the ability of LNPs to effectively encapsulate large-size DNA molecules remains elusive. This is a significant limitation, as the successful delivery of large-size DNA holds immense potential for gene therapy, offering transformative opportunities for the treatment of a wide range of genetic diseases. To address this gap, the present study focuses on the design of PEGylated LNPs, incorporating large-sized DNA, and cationic lipids departing from traditional RNA and ionizable lipids. The resultant LNPs demonstrate a unique particle morphology characterized by distinct layered subunits composed of alternating lipid bilayers and DNA monolayers. Inspired by the ability of DNA to neutralize cationic lipids and promote the formation of an opsonin-deficient protein corona, these particles were further engineered after initial synthesis with a DNA coating and plasma proteins. This novel multicomponent bionanoconstruct exhibits enhanced transfection efficiency and safety in controlled laboratory settings and improved immune system evasion in in vivo tests. This capacity is attributed to its superior ability to evade lysosomal degradation and immune cell capture, a phenomenon that is mediated by a complex interplay among PEGylation, the protein corona, and DNA within the structure. These findings provide valuable insights for the design and development of bionanoarchitectures for large-size DNA delivery, opening new avenues for transformative gene therapies
2024-10-02 | PXD054751 | Pride
Project description:Organ-selective delivery of messenger RNA (mRNA) is critical for fulfilling the therapeutic potential of mRNA-based gene and protein replacement technologies. Despite clinical advances in hepatic delivery of mRNA using lipid nanoparticles (LNPs), strategies for extrahepatic organ-selective mRNA delivery remain underexplored. Here, we report a strategy, termed peptide-encoded organ-selective targeting (POST), that allows digital programming of LNPs, through surface engineering with specific amino acid sequences (POST codes), to deliver mRNA to extrahepatic organs after intravenous administration. Our molecular dynamics simulations also suggest the optimized fracture mechanics of peptide-protein assembly as a mechanism underlying sequence-dependent association between POST code and potentially organ-targeting corona proteins. POST codes are also compatible with organ-selective delivery of different ribonucleic acids and multiple gene editing machineries. This “POST code” platform presents a theoretically unlimited modular repertoire for LNP surface engineering for directing organ-tropism, thereby providing opportunities to broaden the scope and versatility of organ-selective mRNA delivery.
2023-07-20 | PXD043932 |
Project description:Nanozymes play a pivotal role in mitigating excessive oxidative stress, however, determining their specific enzyme-mimicking activities for intracellular free radical scavenging is challenging due to endo-lysosomal entrapment. In this study, we employed a genetic engineering strategy to generate ionizable ferritin nanocages (iFTn), enabling their escape from endo-lysosomes and entry into the cytoplasm. Specifically, ionizable repeated Histidine-Histidine-Glutamic acid (9H2E) sequences were genetically incorporated into the outer surface of human heavy chain FTn, followed by the assembly of various chain-like nanostructures via a two-armed polyethylene glycol (PEG). Utilizing endosome-escaping ability, we designed iFTn-based tetrameric cascade nanozymes with high superoxide dismutase- and catalase-mimicking activities. The in vivo protective effects of these ionizable cascade nanozymes against cardiac oxidative injury were demonstrated in mouse models of cardiac ischemia-reperfusion (IR). RNA-sequencing analysis highlighted the crucial role of these nanozymes in modulating superoxide anions-, hydrogen peroxide- and mitochondrial functions-relevant genes in IR injured cardiac tissue. These genetically engineered ionizable protein nanocarriers provide opportunities for developing ionizable drug delivery systems.
2024-11-21 | GSE282015 | GEO
Project description:Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNP is one approach to avoid these adverse reactions. Herein, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNP, including SS-cleavable and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNP, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better IFN--producing Th1 responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNP conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared to conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less inflammatory responses (e.g., inflammatory cytokine production and vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss and fever) compared with conventional mRNA-LNP. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.
2025-03-05 | GSE279744 | GEO
Project description:Messenger RNA vaccines based on lipid nanoparticles (mRNA-LNPs) are promising vaccine modalities. However, mRNA-LNP vaccines frequently cause adverse reactions such as swelling and fever in humans, partly due to the inflammatory nature of LNP. Modification of the ionizable lipids used in LNP is one approach to avoid these adverse reactions. Herein, we report the development of mRNA-LNP vaccines with better protective immunity and reduced adverse reactions using LNP, including SS-cleavable and pH-activated lipid-like materials with oleic acid (ssPalmO) as an ionizable lipid (LNPssPalmO). We used mRNA expressing H5N1 subtype high-pathogenicity avian influenza virus-derived hemagglutinin or neuraminidase to generate mRNA-LNP vaccines against H5N1 influenza. Compared with conventional LNP, mRNA-LNPssPalmO induced comparable antigen-specific antibodies and better IFN--producing Th1 responses in mice. Both mRNA-LNPssPalmO and conventional mRNA-LNP conferred strong protection against homologous H5N1 virus challenge. In addition, mRNA-LNPssPalmO showed better cross-protection against heterologous H5N1 virus challenge compared to conventional mRNA-LNPs. Furthermore, we observed that mRNA-LNPssPalmO induced less inflammatory responses (e.g., inflammatory cytokine production and vascular hyperpermeability) and fewer adverse reactions (e.g., weight loss and fever) compared with conventional mRNA-LNP. These results suggest that mRNA-LNPssPalmO would be a safe alternative to conventional vaccines to overcome mRNA-LNP vaccine hesitancy.
2025-03-05 | GSE279743 | GEO