Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1069234 | ENA |
REPOSITORIES: ENA
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Project description:CRISPR-based gene editing holds promise for treating genetic diseases, yet its application to lung disorders has been hindered by the challenges of pulmonary delivery. Inspired by the modularity and biocompatibility of amino acid-derived chemistries, we report the combinatorial synthesis of 960 ionizable lipids incorporating chemically diverse backbones from both proteinogenic and non-proteinogenic α-amino acids. Through high-throughput screening and structure-function analysis, we identify CHCha-10, a cyclohexyl amino acid-derived lipid that forms biodegradable nanoparticles capable of efficiently delivering mRNA-based gene editors to lung epithelial cells. Following intratracheal administration, CHCha-10 nanoparticles exhibit enhanced mucus penetration, and epithelial-specific transfection in both mice and ferrets. As a functional application, we demonstrate the first instance of in vivo base editing in the lung via inhalation. Delivery of adenine base editor mRNA and guide RNA targeting the CFTR G542X mutation restores CFTR expression and chloride channel function in G542X human airway epithelial cells, mouse-derived intestinal organoids, and the lungs of cystic fibrosis mice.
2026-03-09 | GSE317845 | GEO
Project description:Endosomal escape is a central barrier to efficient nucleic acid delivery by lipid nanoparticles (LNPs) and remains challenging to quantify in vivo. We report a library of branched ionizable phospholipids (BiPs) that markedly enhance mRNA delivery to the liver. The lead candidate BiP-20 outperformed the clinical benchmark LP01 by 4-fold for CRISPR–Cas9 editing of the TTR gene at low dose with rapid pharmacokinetics. To quantify the endosomal escape kinetics of BiP-20, we used LysoTag mice, which allow immunoisolation of liver lysosomes, and our Lysosomal Barcoding method, finding that ~9% of BiP-20 LNPs reach the cytosol within 30 minutes of administration. Lysosomal proteomics revealed mechanistic regulators of escape and BiP-20–induced alterations in endosomal maturation and recycling pathways. Loss of Rab7, a mediator of late endosomal maturation, increased LNP escape. These findings provide a potent class of ionizable lipids for RNA delivery, a method to quantify endosomal escape in vivo, and mechanistic insight into the endolysosomal determinants of LNP trafficking.
2026-01-20 | PXD072066 | Pride
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