In empty LNP formulations, DSPC–cholesterol resides in outer layers, whereas in loaded systems some of the DSPC–cholesterol is internalized together with siRNA.
Hereditary genetic disorders, cancer, and infectious diseases of the liver affect millions of people around the globe and are a major public health burden. Most contemporary treatments offer limited relief as they generally aim to alleviate disease symptoms. Targeting the root cause of diseases originating in the liver by regulating malfunctioning genes with nucleic acid-based drugs holds great promise as a therapeutic approach. However, employing nucleic acid therapeutics in vivo is challenging due to their unfavorable characteristics. Lipid nanoparticle (LNP) delivery technology is a revolutionary development that has enabled clinical translation of gene therapies. LNPs can deliver siRNA, mRNA, DNA, or gene-editing complexes, providing opportunities to treat hepatic diseases by silencing pathogenic genes, expressing therapeutic proteins, or correcting genetic defects. Here we discuss the state-of-the-art LNP technology for hepatic gene therapy including formulation design parameters, production methods, preclinical development and clinical translation.
Neutralization of the pH (and ionizable lipid) drives the fusion of precursor vesicles into the electron-dense core structures attributed to lipid nanoparticles.
Nanoparticles
are a promising solution for delivery of a wide range
of medicines and vaccines. Optimizing their design depends on being
able to resolve, understand, and predict biophysical and therapeutic
properties, as a function of design parameters. While existing tools
have made great progress, gaps in understanding remain because of
the inability to make detailed measurements of multiple correlated
properties. Typically, an average measurement is made across a heterogeneous
population, obscuring potentially important information. In this work,
we develop and apply a method for characterizing nanoparticles with
single-particle resolution. We use convex lens-induced confinement
(CLiC) microscopy to isolate and quantify the diffusive trajectories
and fluorescent intensities of individual nanoparticles trapped in
microwells for long times. First, we benchmark detailed measurements
of fluorescent polystyrene nanoparticles against prior data to validate
our approach. Second, we apply our method to investigate the size
and loading properties of lipid nanoparticle (LNP) vehicles containing
silencing RNA (siRNA), as a function of lipid formulation, solution
pH, and drug-loading. By taking a comprehensive look at the correlation
between the intensity and size measurements, we gain insights into
LNP structure and how the siRNA is distributed in the LNP. Beyond
introducing an analytic for size and loading, this work allows for
future studies of dynamics with single-particle resolution, such as
LNP fusion and drug-release kinetics. The prime contribution of this
work is to better understand the connections between microscopic and
macroscopic properties of drug-delivery vehicles, enabling and accelerating
their discovery and development.
Fibrin gums up the works
Plasmin is an abundant plasma protease that cleaves and deactivates the clot-associated protein fibrin. Human deficiencies in plasmin and its inactive proenzyme form, plasminogen (PLG), cause severe inflammation in mucosal tissues such as the mouth and eyes. Silva
et al
. report that, like humans, mice lacking plasminogen accumulate extravascular fibrin and develop an oral pathology that phenocopies human ligneous periodontitis (see the Perspective by Vicanolo and Hidalgo). The excess fibrin activates neutrophils through the αMβ2 (Mac-1) integrin receptor, which triggers the production of reactive oxygen species and neutrophil extracellular traps. Additionally, certain human polymorphisms in the PLG gene were found to be associated with increased likelihood of developing periodontitis, suggesting that fibrin–neutrophil interactions may be an attractive target for future treatments of this prevalent disease. —STS
Lipid nanoparticle (LNP) formulations of nucleic acid are leading vaccine candidates for COVID-19, and enabled the first approved RNAi therapeutic, Onpattro. LNP are composed of ionizable cationic lipids, phosphatidylcholine, cholesterol,...
Leukocytes and endothelial cells frequently cooperate to resolve inflammatory events. In most cases, these interactions are transient in nature and triggered by immunological insults. Here, we report that, in areas of disturbed blood flow, aortic endothelial cells permanently and intimately associate with a population of specialized macrophages. These macrophages are recruited at birth from the closing ductus arteriosus and share the luminal surface with the endothelium, becoming interwoven in the tunica intima. Anatomical changes that affect hemodynamics, such as in patent ductus arteriosus, alter macrophage seeding to coincide with regions of disturbed flow. Aortic resident macrophages expand in situ via direct cell renewal. Induced depletion of intimal macrophages leads to thrombin-mediated endothelial cell contraction, progressive fibrin accumulation and formation of microthrombi that, once dislodged, cause blockade of vessels in several organs. Together the findings reveal that intravascular resident macrophages are essential to regulate thrombin activity and clear fibrin deposits in regions of disturbed blood flow.
"Kernel Flux: a whole-head 432-magnetometer optically-pumped magnetoencephalography (OP-MEG) system for brain activity imaging during natural human experiences,"
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