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At least 19 recordsLinked to original sources
PubMed1975

Prevalence of leukokeratosis nicotina palati among 3,819 danes.

Clinical inspection was made of the palatal mucosa of 3,819 patients at the Royal Dental College, Copenhagen. Any occurrence of leukokeratosis nicotina palati (LNP) was recorded, as were the patients' general data and information on their smoking habits. LNP was most prevalent in 30- to 39-year-olds. Prevalence was considerably greater among males than females, even when comparing groups with the same smoking habits. LNP was found in connection with all forms of smoking. In male patients, approx. 30% of pipe smokers had LNP compared with approx. 7% of other smokers. The greatest single factor of importance to the prevalence of LNP, among those who smoked a pipe only, was the level of consumption. The smoking period was of no particular significance. Individual susceptibility is illustrated by the fact that even among pipe smokers with a relatively high consumption, 40% did not exhibit LNP.

Adolescent↗
PubMed2026

Lipid-nanoparticle-mediated base editing of the trabecular meshwork rescues glaucoma in vivo.

Mutations in MYOC, the most common genetic cause of glaucoma, cause misfolded myocilin to accumulate in the endoplasmic reticulum (ER), leading to trabecular meshwork (TM) dysfunction, elevated intraocular pressure, and progressive vision loss. While gene editing offers curative potential, current delivery methods rely on viral vectors, which are limited by inflammation, off-target effects, and poor translatability. Here, we report a nonviral lipid nanoparticle (LNP) platform that enables selective in vivo delivery of mRNA encoding an adenine base editor and single guide RNA (LNP-ABE) to TM cells. A direct comparison of LNP-mCherry with lentiviral GFP revealed that LNPs outperform viral vectors, achieving markedly higher efficiency and greater selectivity for the TM without inducing ocular inflammation. In a Cre-inducible Tg.CreMYOCY437H glaucoma mouse model, LNP-Cre mRNA selectively induced mutant MYOC expression in the TM, faithfully recapitulating key disease features. A single administration of LNP-ABE achieved efficient on-target editing of mutant MYOC, reducing mutant myocilin protein by approximately 46%, decreasing aggregates, alleviating ER stress, and fully rescuing the glaucomatous phenotype in Tg.CreMYOCY437H mice. Importantly, no off-target editing or ocular toxicity was detected. These findings establish LNP-based mRNA delivery as a safe, efficient, and clinically translatable approach for TM-targeted genome editing with broad therapeutic potential in glaucoma.

Animals↗
PubMed1990

Topographic variations in W-cell input to cat superior colliculus.

Most of the retinal input to the cat's superior colliculus (SC) arises from W-cells of the contralateral eye and terminates just below the tectal surface. The goal of this study was to determine whether the strength of this input is uniform over the collicular map or, instead, exhibits topographic variations as has been reported for the retinotectal Y-cell projection (McIlwain and Lufkin 1976). Monosynaptic inputs from the principal W-cell projection mediate the late negative potential (LNP), a collicular field potential that can be evoked by shocks to the optic pathway. We assumed that the amplitude of the potential provided a measure of the strength of the W-cell input to the upper superficial gray layer. Using a fixed stimulus, we measured the maximal amplitude of the LNP at 90 topographically identified tectal sites in 5 cats. The amplitude of the LNP varied as much as 5-fold over the SC and was systematically related to the azimuthal position of the recording site. LNP amplitudes were consistently smallest in the representation of the area centralis and vertical meridian and largest in the representations of the contralateral hemifield periphery and the ipsilateral hemifield. There was little systematic variation in LNP amplitude as a function of elevation in the map. The observed variations did not result from non-uniform activation of retinal afferents or drift in properties of the recording electrodes, stimuli, or preparation. The results suggest that the principal W-cell input to the SC is weaker in the representation of the area centralis than elsewhere in the map.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1985

Light and electron microscopy study of fusion of facial prominences. A distinctive type of superficial cells at the contact sites.

The contact site between the medial nasal prominence (MNP) and the lateral nasal prominence (LNP) during the period of primary palate formation in the mouse embryo was examined by light and electron microscopy. Throughout this period, a distinctive type of superficial cell was observed at the contact site. These superficial cells had a large nucleus and abundant cytoplasm as well as structural features characteristic of embryonic cells. At earlier stages, these cells were seen at the transitional region between the surface ectoderm and the epithelia of the nasal pit at the end of the isthmus, where initial contact of opposing MNP and LNP took place. At later stages, these superficial cells appeared to bridge the gap between MNP and LNP at the contact sites, which extended to the bottom of the valley formed by MNP and LNP. These cells were also observed on the surface near the contact sites, that is, the presumptive fusion area. These superficial cells displayed well-developed junctional complexes (intermediate and gap junctions, and desmosomes). Many filaments were observed subjacent to the plasma membranes of these superficial cells, some of which were associated with junctional complexes. These observations suggest that this kind of distinctive superficial cell may play critical roles in the contact of MNP and LNP throughout the fusion process.

Animals↗
PubMed2025

Validation of breast cancer as a risk factor for anxiety and depression: Insights from Mendelian randomization analysis.

This study employed Mendelian randomization (MR) analysis to confirm the association between breast cancer and the risk of anxiety and depression, and to explore the molecular mechanisms by which lipid nanoparticles of ketamine (LNP@Ket) modulate these behaviors in a mouse model of breast cancer. Through single-cell transcriptomic analysis, the study aimed to clarify nuclear factor erythroid 2-related factor 2 (Nrf2)'s role in the development of anxiety and depression in these mice. Analysis of patient data from genome-wide association study (GWAS) databases supported the link between breast cancer, anxiety, and depression. In vivo experiments demonstrated that treating breast cancer mice with LNP@Ket significantly reduced anxiety and depression behaviors. The synthesis of LNP@Ket and its subsequent analysis highlighted its inhibitory effects on these behaviors. Single-cell transcriptomic sequencing identified key cells and genes affected by LNP@Ket treatment, particularly emphasizing Nrf2. Upregulation of Nrf2 in astrocytes increased the expression of antioxidant enzymes and reduced pro-inflammatory cytokines, alleviating anxiety and depression symptoms by inhibiting neuroinflammation and neurodegeneration. This comprehensive study highlights the pivotal role of Nrf2 in the therapeutic efficacy of LNP@Ket for treating anxiety and depression in breast cancer mice.

Anxiety and depression behaviors↗
PubMed2024

Lung and liver editing by lipid nanoparticle delivery of a stable CRISPR-Cas9 ribonucleoprotein.

Lipid nanoparticle (LNP) delivery of clustered regularly interspaced short palindromic repeat (CRISPR) ribonucleoproteins (RNPs) could enable high-efficiency, low-toxicity and scalable in vivo genome editing if efficacious RNP-LNP complexes can be reliably produced. Here we engineer a thermostable Cas9 from Geobacillus stearothermophilus (GeoCas9) to generate iGeoCas9 variants capable of >100× more genome editing of cells and organs compared with the native GeoCas9 enzyme. Furthermore, iGeoCas9 RNP-LNP complexes edit a variety of cell types and induce homology-directed repair in cells receiving codelivered single-stranded DNA templates. Using tissue-selective LNP formulations, we observe genome-editing levels of 16‒37% in the liver and lungs of reporter mice that receive single intravenous injections of iGeoCas9 RNP-LNPs. In addition, iGeoCas9 RNPs complexed to biodegradable LNPs edit the disease-causing SFTPC gene in lung tissue with 19% average efficiency, representing a major improvement over genome-editing levels observed previously using viral or nonviral delivery strategies. These results show that thermostable Cas9 RNP-LNP complexes can expand the therapeutic potential of genome editing.

Gene Editing↗
PubMed1986

Changes in the subepithelial mesenchymal cell process meshwork in developing facial prominences in mouse embryos.

We examined temporal and spatial changes in the subepithelial mesenchymal cell process meshwork (CPM) in normally developing medial (MNP) and lateral nasal prominences (LNP) in mouse embryos by light and scanning electron microscopy. Marked changes were found only in the MNP during the fusion of the MNP and LNP. The CPM density in the prospective fusion area of the MNP gradually increased as the epithelial surfaces approached each other, attained its maximum just before contact, and decreased after contact. The CPM density in the prospective fusion area of the LNP changed only slightly even when the epithelial surfaces approached each other. The increase in CPM density paralleled that in the density of mesenchymal cell bodies. The LNP grew more actively toward the line of fusion than did the MNP during the progressive fusion of the two prominences. A larger number of fusion-associated epithelial morphological changes--the appearance of superficial protruding cells and cell degeneration--occurred in the MNP than in the LNP. These findings suggest that the increased CPM density is closely related to the growth of the facial prominences and the fusion-associated epithelial morphology and that the CPM plays an important role in the epithelial-mesenchymal interaction during the formation of the upper lip and primary palate.

Animals↗
PubMed2026

Ligand-Mediated Reprogramming Redirects Liver-Tropic Ionizable Lipid Nanoparticles for Lung-Selective mRNA Delivery.

Systemic delivery of messenger RNA (mRNA) to target tissues and cells using lipid nanoparticles (LNPs) holds transformative potential for gene therapy. However, most clinically validated LNP exhibit strong liver tropism, and redirecting their organ specificity without redesigning entirely new chemistries remains challenging. Here we present a ligand-mediated lipid reprogramming approach that repurposes chemically defined, liver-tropic, ionizable lipids (lipidoids) for mRNA delivery beyond the liver. From a library of 90 degradable lipidoids, we identified 2-t6b as a potent liver-targeting platform. By site-specific displaying of small molecule ligands onto 2-t6b headgroup, we engineered a series of reconfigured lipidoids that achieve lung-specific targeting while retaining the parent delivery scaffold. Ligand7-2-t6b-lipid-functionalized LNP achieved over 200-fold higher mRNA translation in the lungs compared to the parent liver-tropic LNP. Proteomics and molecular docking analysis revealed enhanced binding of the modified lipid to vitronectin, a serum glycoprotein that improves integrin binding and thus promotes cellular uptake and translation efficiency. Ligand-mediated 2-t6b/ligand7 LNPs achieved outperformed efficacy and therapeutic potential in lung-specific genome editing relative to SORT-constructed 2-t6b LNP system. Our modular reprogramming strategy provides a generalizable framework to upgrade existing liver-biased LNPs into lung-selective mRNA carriers, advancing next-generation tissue-specific mRNA therapies for gene editing, protein replacement therapy, and regenerative medicine.

RNA, Messenger↗
PubMed2026

Efficient prime editing in vivo and in vitro using lipid nanoparticles.

Prime editing is a versatile clinical genome editing method that enables precise substitutions, small insertions and deletions at specified locations in the genomes of living systems including human cells. Although non-viral lipid nanoparticle (LNP) delivery of RNA in vivo has become a preferred method for gene editing in animals and patients, its application to complex, three-component prime editing systems has yielded low editing efficiencies. Here we developed a systematic prime editing LNP (PE-LNP) optimization platform that addresses key bottlenecks in cargo design that limit editing efficiency. This generalizable workflow yielded PE-LNPs that can achieve 49% average in vivo prime editing in the bulk mouse liver with a single dose of 2 mg kg-1. We applied our workflow to the correction of PAH R408W, a cause of phenylketonuria, in a mouse model and achieved prime editing efficiencies and serum phenylalanine levels anticipated to be curative. We also show that PE-LNPs minimize off-target editing compared with DNA delivery methods, induce only transient elevation of liver enzymes and can be dosed repeatedly to improve editing efficiencies. These PE-LNP systems provide an attractive alternative to viral delivery by offering transient expression that minimizes off-target editing, no observed long-term toxicity and high levels of non-viral in vivo liver prime editing.

Animals↗
PubMed2026

Enhancing Lipid Nanoparticle-Mediated Circular RNA and mRNA Expression in the Placenta through Inhibition of IFNAR-JAK-STAT Signaling.

The placenta has emerged as a promising target for RNA lipid nanoparticle (LNP)-based therapies to treat obstetric complications, yet efficient extrahepatic RNA transfection remains a challenge. Here, we identify innate immune signaling as a regulator of placental RNA translation and demonstrate that inhibition of IFN-α/β receptor (IFNAR) and JAK-STAT signaling enhances LNP-mediated transgene expression in the placenta for both messenger RNA (mRNA) and circular RNA (circRNA). While a placenta-tropic LNP enabled robust and durable circRNA expression in trophoblasts in vitro, circRNA translation was substantially decreased in vivo compared to mRNA in pregnant mice. Inhibition of IFNAR-JAK-STAT signaling enhanced circRNA translation up to 12-fold in maternal organs and increased circRNA and mRNA translation in the placenta up to 17.5- and 4-fold, respectively. JAK-STAT inhibition also enhanced translation of therapeutically relevant VEGF-encoding circRNA and mRNA in pregnant mice, suggesting innate immune modulation as a broadly applicable strategy to improve RNA therapeutics during pregnancy.

Female↗
PubMed2024

Accelerating diabetic wound healing by ROS-scavenging lipid nanoparticle-mRNA formulation.

Current treatment options for diabetic wounds face challenges due to low efficacy, as well as potential side effects and the necessity for repetitive treatments. To address these issues, we report a formulation utilizing trisulfide-derived lipid nanoparticle (TS LNP)-mRNA therapy to accelerate diabetic wound healing by repairing and reprogramming the microenvironment of the wounds. A library of reactive oxygen species (ROS)-responsive TS LNPs was designed and developed to encapsulate interleukin-4 (IL4) mRNA. TS2-IL4 LNP-mRNA effectively scavenges excess ROS at the wound site and induces the expression of IL4 in macrophages, promoting the polarization from the proinflammatory M1 to the anti-inflammatory M2 phenotype at the wound site. In a diabetic wound model of db/db mice, treatment with this formulation significantly accelerates wound healing by enhancing the formation of an intact epidermis, angiogenesis, and myofibroblasts. Overall, this TS LNP-mRNA platform not only provides a safe, effective, and convenient therapeutic strategy for diabetic wound healing but also holds great potential for clinical translation in both acute and chronic wound care.

Wound Healing↗
PubMed1987

Origin of short latency somatosensory evoked potential in cats: especially potentials derived from thalamus and cortex.

Short latency somatosensory evoked potential (SSEP) was recorded in cats to identify the potentials originating from the cortex and the thalamus, and the following results were obtained. When SSEP was elicited on the bregma by stimulation of the contralateral superficial radial nerve, P2, P4, P4.5, P5.5, P7, P8, N8.5, P11, P9.5, N11.5, N12.5 and N14 were recognized. Of these components N11.5, N12.5 and N14 consisted of large negative potential (LNP). When KCl was applied to the sensorimotor cortex to induce spreading depression, the positive component of the primary evoked potential was markedly decreased and the negative component disappeared. In SSEP, components preceding N8.5 were unchanged. N8.5-P11 and P11-N12.5, however, markedly diminished or disappeared. The latency of the first component of the field potential recorded in the VPL nucleus of the thalamus was about 5 ms. When a small amount of Nembutal was injected into VPL nucleus, components between P2 and P4.5 remained unchanged, but P5.5 disappeared. P7, P8 and N8.5 were preserved. The amplitude of N8.5-P11 was markedly decreased and LNP disappeared. From these results, among various components of SSEP, P5.5 should originate from the thalamus, and P7, P8 and N8.5 from the extralemniscal system. N8.5-P11 should mainly represent post-synaptic potential (PSP) in the deep somatic layer, and P11-N12.5 represent PSP in the apical dentrites of the sensorimotor cortex. N14 probably represents PSP via the diffuse projection system. Thus, LNP should consist of complex potentials of specific and non-specific sensory systems.

Animals↗
PubMed2026

A modular γδ TCR-T platform combining KRAS pMHC targeting with re-dosable mRNA engager redirection.

Solid tumors often evade TCR-engineered αβ T cells when antigen expression varies or when the restricting Human Leukocyte Antigen (HLA) allele is lost. γδ T cells, in contrast, detect cellular dysregulation through non-peptide/Major Histocompatibility Complex (MHC) cues, including phosphoantigens and stress ligands, and can be developed as allogeneic therapies. Although intratumoral γδ T cell signatures are associated with improved outcome across cancers, γδ recognition itself is broad and still selected within the thymus just as αβ T cell receptors (TCRs) are. It does not, however, anchor specificity to a defined driver-mutation pMHC epitope. We therefore asked whether a high-affinity, co-receptor-independent αβ TCR could graft oncogenic-driver specificity onto γδ T cells while leaving the endogenous γδ TCR intact. We knocked the KRASG12V/HLA-A*11:01 TCR A11v into primary human γδ T cells. Engineered cells co-expressed the transgenic αβ TCR and the endogenous γδ TCR and lysed KRASG12V/HLA-A*11:01+ tumor cells in vitro and in vivo. To cover potential resistance through loss of HLA-A*11:01, we delivered an mRNA lipid nanoparticle (LNP) encoding a secreted mesothelin×CD3 (M5) bispecific T cell engager (TCE). LNP-M5 produced circulating TCE that redirected γδ A11v T cells and polyclonal bystander T cells to kill mesothelin+ targets, accompanied by development of higher γδ A11v T cell counts in vivo. In humanized mice bearing mixed HLA-A*11:01+ and HLA-A*11:01 - KRASG12V tumors, γδ A11v T cells produced transient control, whereas adding LNP-M5 yielded complete responses and prolonged survival. Thus, this two-part therapy couples invariant driver targeting to tunable redirection and addresses loss of the restricting HLA allele, a central escape route for TCR-based therapy. It provides an off-the-shelf reagent to enable KRAS-anchored treatment with the ability to redeliver the reagent.

Humans↗
PubMed1991

Inflammatory response induced with an isolated syngeneic activation antigen shared by normal lymphoblasts and YAC lymphoma cells.

An immunogenic protein with an identical Mr (64 kDa) was isolated from syngeneic concanavalin A-induced lymphoblasts (syn-Con A-blasts) and YAC lymphoma cells, both derived from A mice. The 64-kDa protein was purified by a sequence of biochemical steps: Sephadex G-100 gel filtration, ion-exchange chromatography in a fast protein liquid chromatography system, Con A-Sepharose affinity chromatography, and preparative gel electrophoresis. The immunogenic fraction isolated in each step was moved to the next one, and so on. The immunogenicity of the separated fractions was measured by a lymph node proliferation (LNP) assay, which is indicative of a delayed-type hypersensitivity response. For instance, the final 64-kDa isolated protein of the syn-Con A-blasts induced an efficient LNP response in A mice which was detected after challenge with the final 64-kDa isolated protein of YAC cells. In addition to their identical molecular weight, both proteins were eluted at the same ionic strength and both expressed affinity to Con A-Sepharose beads, suggesting that they were glycosilated. Similar 64-kDa proteins were isolated by a different purification procedure, which was performed in the presence of protease inhibitors, excluding the possibility that the final antigen was an autodigested product. As the 64-kDa protein is immunogenic in the syngeneic host, it may be employed as a immunotherapeutic reagent against the original tumor and perhaps against other tumors expressing the same antigen.

Animals↗
PubMed2025

Strain-Promoted mRNA Transdermal Delivery by Lipoic Lipid Nanoparticles for Therapeutic Skin Genome Editing.

Lipid nanoparticle (LNP)-mRNA formulations have revolutionized the field of nucleic acid therapeutics, yet their broader clinical application is constrained by inflammatory side effects and oxidative stress, particularly in the context of inflammatory diseases. Herein, we report the rational design and synthesis of a lipoic acid-based ionizable lipid library to address these limitations. By leveraging the antioxidant properties and thiol-mediated uptake potential of lipoic acid, we identified LA-A2B2CD3 as an optimal candidate through a structure-activity relationship study and design of experiment (DOE) optimization. LA-A2B2CD3 LNPs exhibited superior reactive oxygen species scavenging, enhanced mRNA translation, and reduced inflammatory cytokine production in vitro and in vivo. Mechanistic studies revealed that the efficient cellular uptake and the transdermal delivery capacity of LA-A2B2CD3 heavily rely on the reducible disulfide ring of lipoic acid. Application of LA-A2B2CD3 LNPs for the localized transdermal delivery of Cas9 mRNA and CD93 sgRNA in a murine model of psoriasis resulted in effective CD93 genome editing and the inhibition of the CD93-p38 MAPK-AKT-SMAD2/3 pathway, leading to significant therapeutic improvement. This work presents a robust, biocompatible LNP platform with minimized immunogenicity and strong potential for genome-editing therapies in inflammatory conditions, offering a transformative approach for the mRNA-based treatment of skin and other inflammation-related disorders.

Animals↗
PubMed2026

Influence of protein aggregates, extracellular vesicles, and lipoprotein fusion on ionizable lipid nanoparticles protein corona analysis.

Since 2018, ionizable lipid nanoparticles (LNPs) have revolutionized nucleic acid therapeutics. However, achieving potent extrahepatic delivery remains a formidable challenge, primarily due to rapid hepatic uptake driven by apolipoprotein adsorption. While analyzing the LNP protein corona is essential for engineering organ-specific tropism, these soft materials present unique analytical hurdles. Co-isolation of blood-borne contaminants, such as extracellular vesicles and lipoproteins, often masks the true corona composition. This perspective examines the critical need for refined proteomic strategies to distinguish genuine corona proteins from impurities. We propose tailored investigative approaches, suggesting the LNP protein corona significantly differs from the rigid shells observed on inorganic nanoparticles.

Nanoparticles↗
PubMed2026

Charge-switching ionizable lipids lower the toxicity of lipid nanoparticles.

Lipid nanoparticles (LNPs) have great potential as nucleic acid delivery vehicles; however, they trigger the production of inflammatory cytokines, which limits their medical applications. Developing non-inflammatory LNPs is challenging because the LNP's ionizable lipid and the process of endosomal disruption are the major sources of LNP toxicity but are also essential for delivering nucleic acids. Here we demonstrate that ionizable lipids containing a carboxylic acid and an amine (termed S-lipid) switch their charged state between the pHs of 7.4 and 4.0, allowing them to generate LNPs (termed switchable nanoparticles) that efficiently encapsulate nucleic acid and trigger endosomal release without activation of the TLR4, complement, galectin-8 and platelet activating factor signalling pathways. Finally, we demonstrate that switchable nanoparticles are better at treating lipopolysaccharide-induced acute lung injury than traditional LNPs because they do not exacerbate pre-existing inflammation. Collectively, these results demonstrate that negatively charged ionizable lipids can mitigate the toxicity of LNPs.

Journal Article↗
PubMed2026

mRNA vaccine immunity is enhanced by hepatocyte detargeting and not dependent on dendritic cell expression.

Proteins encoded by mRNA vaccines can be expressed by a diversity of transfected cell types but how cell-type-specific expression influences immunity is poorly understood. To investigate this, we incorporated synthetic microRNA target sites (miRT) into lipid nanoparticle (LNP)-delivered mRNA vaccines to silence mRNA expression specifically in professional antigen-presenting cells (pAPCs), hepatocytes or myocytes. We found that mRNA expression in pAPCs was dispensable for priming antigen-specific T cells, whereas mRNA expression in myocytes induced similar or stronger immune responses, including for SARS-CoV-2, suggesting that antigen cross-presentation or cross-dressing may be more impactful than direct mRNA expression in pAPCs. In contrast, mRNA expression in hepatocytes suppressed the antigen-specific T cell response, partly through PD1/PDL1. In mice bearing tumor-associated antigen (TAA)-expressing lymphoma cells, miRT-mediated hepatocyte-silenced TAA mRNA vaccine enhanced immune response and reduced tumor burden. Thus, non-pAPC expression shapes immunity to mRNA-encoded protein and inclusion of miRTs can boost or blunt mRNA-LNP immunogenicity.

Journal Article↗