Biology subjects

Wang, J.

Publications and source records attributed to Wang, J..

At least 577 records · Page 32Linked to original sources

bioRxiv2025

Local translation of circular RNAs is required for synaptic activity and memory

Circular RNAs (circRNAs) are enriched in synapses and implicated in cognitive processes, and recent studies have shown that circRNAs can encode micropeptides, which suggests that there may be novel synaptic proteoforms in the brain that await discovery. Here we report widespread learning-induced local circRNA translation in the prefrontal cortex of male C57BL/6 mice. More than 1500 synapse-enriched circRNAs contain active IRES elements, with 842 interacting with the ribosome and 241 exhibiting direct evidence of activity-induced translation. We discovered a synapse-enriched micropeptide (P1) that is derived from a single exon circRNA, the mRNA host of which encodes an enzyme associated with protein repair. Although P1 is only a third of the size of the full-length protein, it is locally expressed, enzymatically active, and interacts with plasticity-related proteins, including CaMKII. In addition to direct effects on synaptic activity, targeted P1 knockdown impairs whereas its overexpression enhances fear extinction memory. These findings shed new light on the dark proteome in the brain and reveal local circRNA translation as a novel mechanism of plasticity and memory.

neuroscience↗

bioRxiv2025

Building an Ecosystem of Seizure Localization Methods: Neural Fragility as the First Step

The current treatment for drug-resistant epilepsy (DRE) is surgical intervention, which relies on accurate identification of the seizure onset zone (SOZ) using intracranial EEG (iEEG) data. iEEG analysis with computational epileptogenic zone identification algorithms (CEZIAs) is a promising step towards better SOZ localization and surgical outcomes. A key step in validation and adoption of CEZIAs is to allow for widespread shared development and validation of code and data. We describe a set of three R packages to achieve this goal. Our ecosystem of seizure localization methods involves a straightforward analysis pipeline, standardized data formatting and storage, and completely documented and open-source code. The TableContainer package allows for easy storage and manipulation of table data, serving as groundwork for the Epoch package, which is specifically geared towards iEEG data. The Epoch package allows for cropping, resampling, and visualization of iEEG data and provides publicly downloadable iEEG data for reproducibility. Finally, the EZFragility package uses these two foundational packages to analyze iEEGs for SOZ localization using the Neural Fragility method described by Li et al. EZFragility was built using the same core principles as the original method but included several enhancements in computational efficiency and user experience. It accurately reproduces neural fragility results for both sample patients used in the original paper. This project serves as the first step towards building an open-source, reproducible ecosystem of seizure localization methods in R. Future steps include the addition of other CEZIAs using the framework and sample data already made available by these packages. Significance StatementLocalization of the seizure onset zone (SOZ) is a critical step in surgical treatment of drug-resistant epilepsy. Computational epileptogenic zone identification algorithms (CEZIAs) are promising potential tools to aid in clinical decision-making. However, shared development and verification of CEZIAs is difficult due to obscured source code, variable data structures, and limited data availability. The EZFragility software package1 is the first step in building a collaborative ecosystem of CEZIAs that can be downloaded, tested, and used without these roadblocks. EZFragility1 and its dependent packages TableContainer2 and Epoch3 are freely available on the Comprehensive R Archive Network (CRAN), with source code viewable on GitHub. They provide an open-source framework for CEZIA code, data formatting, and data access, all with extensive documentation.

neuroscience↗

bioRxiv2025

HUBMet: An integrative database and analytical platform for human blood metabolites and metabolite-protein associations

Understanding human blood metabolites is essential for deciphering systemic physiology and disease mechanisms, yet remains challenging due to diverse origins and dynamic regulation. In this study, we developed HUBMet (https://hubmet.app.bio-it.tech/home), an open-access web server that includes 3,950 metabolites and 129,814 metabolite-protein associations, with four analytical modules: Over-Representation Analysis (ORA) for enrichment analysis; Metabolite Set Enrichment Analysis (MSEA) for quantitative data analysis; Tissue Specificity Analysis (TSA) for assessing metabolite-tissue relevance; Metabolite-Protein Network Analysis (MPNet) for identifying key metabolite-protein associations and functional modules. HUBMets utility is demonstrated through a COVID-19 case study revealing metabolic signatures associated with disease severity.

bioinformatics↗

bioRxiv2025

Embryonic Atrial Injury Programs an Anti-Fibrotic Atrial Fibrillation Substrate

Atrial myopathy is associated with atrial fibrillation in adults, yet the role of embryonic atrial injury in predisposing individuals to atrial fibrillation remains unclear. Using an inducible, cardiomyocyte-specific diphtheria toxin A-mediated injury mouse model, we found that injured embryonic atria exhibited upregulation of apoptosis and TNF signaling pathways, alongside downregulation of calcium handling and atrial fibrillation-associated genes. Single-cell RNA sequencing revealed two distinct cardiomyocyte populations with differential injury responses. Importantly, although myofibroblasts increased in the fibroblast population, these cells displayed an extracellular matrix gene expression profile distinct from the pro-fibrotic phenotype typically observed in fibrillating adult atria and showed no evidence of fibrosis. Concurrently, monocytes/macrophages were activated and showed upregulated expression of the anti-fibrotic factor GPNMB. These findings suggest that adaptive tissue remodeling is counterintuitively prevented from progressing to fibrosis, potentially through GPNMB-mediated mechanisms. This study elucidates molecular pathways linking developmental atrial injury to myopathy and proposes novel strategies to attenuate atrial fibrillation progression.

pathology↗

bioRxiv2025

Sarbecovirus Rc-o319 S-Protein Structures Reveal Highly Specialized Adaptation to Rhinolophus cornutus ACE2

Bat sarbecoviruses often exhibit species-dependent ACE2 specificity. Understanding the determinants of receptor specificity enables better assessment of the cross-species transmission potential of sarbecoviruses. Here, we characterize the S-protein of Rc-o319, a sarbecovirus identified in Japanese Rhinolophus cornutus bats. Featuring an unusual 9-amino-acid deletion within its receptor binding motif (RBM), Rc-o319 S-protein utilizes its cognate R. cornutus ACE2 (bACE2R.cor) but not human ACE2 (hACE2), demonstrating highly restricted receptor specificity. Cryo-EM structures reveal two locked prefusion conformations of the Rc-o319 S-trimer and define a novel type-1b receptor-binding domain (RBD), featuring a distinct beta-loop (BL) within the RBM due to the RBM-deletion. The Rc-o319-RBD:bACE2R.cor complex structure reveals unique interactions mediated by the specialized BL and RBM-loop of Rc-o319-RBD and by a bACE2R.corglycan. Structure-guided mutagenesis demonstrates that changes in BL and RBM-loop within the Rc-o319 S-RBD must occur simultaneously to allow medium-to-high-affinity hACE2 binding. Comparative assays further show that the bACE2R.cor receptor supports only a subset of sarbecoviruses, highlighting its restricted sarbecovirus compatibility. Our findings establish the Rc-o319 S-protein as a structurally and functionally specialized adaptation to R. cornutus ACE2 and identify the structural constraints limiting its cross-species transmission potential. Author SummarySARS-related viruses are widely found in horseshoe bats. Some can bind the human ACE2 receptor with variable affinities, whereas others bind only bat ACE2 receptors. Understanding the basis for this difference is critical for assessing spillover risk. We studied the spike protein of a bat sarbecovirus, Rc-o319, isolated from Japanese Rhinolophus cornutus horseshoe bats. Although Rc-o319 is genetically related to SARS-CoV-2, it is unable to bind the human ACE2 receptor. Structural analyses and functional experiments revealed that the Rc-o319 spike protein possesses a distinct receptor-binding motif (RBM). This RBM features a specialized "beta-loop" that replaces the "large-loop" found in human-infecting sarbecoviruses. The beta-loop enables high-affinity binding to its cognate Rhinolophus cornutus bat ACE2 receptor while simultaneously preventing optimal interaction with human ACE2. We further found that acquisition of high affinity for the human ACE2 receptor would require coordinated changes across multiple regions of the RBM, including changing the beta-loop into a large-loop structure. Together, our findings demonstrate that the Rc-o319 spike protein is highly adapted to its cognate bat ACE2 receptor and faces substantial structural constraints that limit its ability to switch to binding human ACE2.

microbiology↗

bioRxiv2025

SIMple: A fibre-based platform for accessible structured illumination microscopy

Structured illumination microscopy can be used to achieve optical sectioning and super resolution in fluorescence images, reducing out-of-focus light and increasing the resolution beyond the diffraction limit, without the need for specialised detection optics. However, the complex illumination path is difficult to build and align. We present an illumination path based on fibre-optic components for both splitting and phase-shifting the illumination light. This enables a SIMple and compact "Plug&Play" modality which substantially reduces the time and alignment required when adding the optics to an existing widefield instrument. The system is capable of optical sectioning imaging at camera-limited frame-rates using multiple excitation wavelengths simultaneously, as demonstrated by imaging fixed and live biological samples at 561 and 491 nm. Super-resolution imaging of fixed samples on a very compact, self-contained microscope is also demonstrated: illumination is coupled in by fibre to a lightweight frame with dimensions of just 300 x 450 x 300 mm3, enabling easy transportation and use in laboratories with limited space. Characterisation of the system using bead analysis shows a resolution of 168 and 172 nm at 491 and 561 nm, respectively, an improvement by a factor of 1.91 and 1.92 compared to widefield, with a field of view of 100 x 100 {micro}m2.

bioengineering↗

bioRxiv2025

JointMap identified SERPINA3+ chondrocytes as a therapeutic target for osteoarthritis

BackgroundOsteoarthritis (OA) is a prevalent degenerative joint disease that affects nearly half of the population aged over 65. Recent single-cell transcriptional studies have identified heterogeneous OA-specific chondrocyte subtypes, yet a unified subtype-classification remains incomplete. MethodsIn this study, we integrated a total of 545,946 cells to develop JointMap, an interspecies atlas. The chondrocyte subtypes were analyzed using machine learning algorithms were validated via human samples, animal models, and in vitro cell culture. We performed KAS-seq and analyzed the spatial characters for JointMap. ResultsBased on clinical diagnosis and cross-omic indexes, we identified a novel OA-elevated chondrocyte subtype, SERPINA3+ chondrocytes. Notably, we uncovered their upregulated chondrogenesis function and intercellular communication patterns as potential therapeutic targets. ConclusionsIn summary, JointMap provides a unified framework for the systematic annotation of chondral tissues across species and helps in the identification of druggable networks for articular diseases.

bioinformatics↗

bioRxiv2025

ODC1 restricts meningeal B cell age-associated-like phenotype and function in multiple sclerosis: a human and experimental study

Meningeal inflammation, as a clinical feature of multiple sclerosis (MS), is associated with worse clinical disease outcomes. In both relapsing and secondary progressive MS and the experimental autoimmune encephalomyelitis (EAE) MS model, the meninges have been found to contain ectopic lymphoid follicles enriched with B cells. The metabolic requirement of meningeal B cell function in MS or EAE is not well elucidated. Using 7-Tesla MRI brain scans of MS patients and leptomeningeal enhancement (LME) as a marker, we found a correlation between meningeal inflammation and metabolites of the arginine/polyamine pathway, a finding recapitulated in the EAE model. Ornithine Decarboxylase (ODC1), the rate limiting enzyme for polyamine biosynthesis, as well as polyamine metabolism was diminished in the dura meningeal B cells from mice with MOG35-55 induced EAE mice as compared to naive controls. Pharmacological inhibition of ODC1 restricted meningeal T cells but promoted meningeal B cell proliferation. B cell-specific deletion of ODC1 resulted in expansion of B cells with age-associated B cell-like phenotype (CD11c+CD21/35-CD23-IgD-) and exacerbated disease in the MOG1-125 EAE model. Together, these findings demonstrate a divergent role of polyamines in regulating B and T cell responses in the meninges during autoimmunity. Significance StatementThis study identified the polyamine pathway to be associated with meningeal inflammation in multiple sclerosis, a clinical phenotype associated with worse disease outcomes and without targeted therapy. Using a mouse experimental model, we found that ODC1, the rate limiting enzyme of the polyamine biosynthesis pathway, was suppressed in meningeal B cells, restricted the development of age-associated B cells in the meninges and limited disease severity. This study elucidated a metabolic pathway regulating meningeal B cell function, informing its therapeutic applications in autoimmune diseases.

immunology↗

bioRxiv2025

PGRP-LA regulates peritrophic matrix synthesis and influences trypanosome infection outcomes in tsetse flies

Peptidoglycan Recognition Proteins (PGRPs) are conserved pattern-recognition receptors that detect microbe-associated molecular patterns (MAMPs) and activate host immune responses. Compared to other dipterans, the tsetse fly (Glossina morsitans morsitans) genome encodes only five PGRPs-PGRP-LA, -LB, -LC, -SA, and -SB - far fewer than most dipterans, likely reflecting its sterile blood diet and streamlined microbiota. Here, we identify PGRP-LA as a critical regulator of peritrophic matrix (PM) integrity in the cardia (proventriculus), the tissue responsible for PM production. The PM is a chitinous sleeve-like barrier that separates the midgut epithelium from the ingested bloodmeal, supporting digestive homeostasis and infection resistance. We show that pgrp-la is prominently expressed in the cardia, transiently induced after a bloodmeal in newly eclosed flies, and reinduced following subsequent feedings, likely in response to blood-constituents or mechanical stretch. This induction is sustained during microbial exposure and prolonged in trypanosome-infected flies. RNAi-mediated reduction of pgrp-la significantly increased the prevalence of midgut trypanosome infections, indicating a protective role during early infection. PGRP-LA did not mediate infection resistance via canonical IMD pathway signaling, as its silencing did not affect antimicrobial peptide expression. Instead, PGRP-LA modulated the expression of PM-associated genes and gut barrier integrity. Silencing pgrp-la reduced PM structure, increased midgut weights and enhanced fly survival following oral challenge with entomopathogen Serratia marcescens, likely due to earlier epithelial immune responses through a compromised PM. Similar phenotypes were observed when flies were fed anti-PGRP-LA antibodies, supporting a structural role for PGRP-LA. In addition, soluble variant surface glycoproteins (sVSGs) from trypanosomes and knockdown of microRNA-275 (miR-275), also decreased pgrp-la expression, suggesting that PGRP-LA is part of a broader regulatory network, including the miR-275/Wingless signaling. Collectively, our results identify PGRP-LA as novel regulator of PM biogenesis and vector competence in tsetse, expanding the functional repertoire of PGRPs in insect gut barrier maintenance beyond canonical immune signaling pathways. Author SummaryInsect vectors such as tsetse flies can be infected with pathogens that cause devastating disease in mammals. To protect themselves insect vectors rely on pattern recognition receptors (PRRs) that detect pathogens and activate the production of antimicrobial peptides (AMPs). Physical barriers in the gut also play an important role in limiting infections. One such barrier is the peritrophic matrix (PM), a sleeve-like structure that lines the insect gut and separates the blood meal and its contents from the underlying cells. For trypanosome parasites, which cause sleeping sickness in humans, the PM is the first barrier they must traverse to colonize the tsetses gut. In this study, we identified a PRR, PGRP-LA, that, unlike related proteins in other insects that activate AMPs, regulates the integrity of the tsetses protective PM barrier. When PGRP-LA was disrupted, the gut barrier weakened, and flies became more susceptible to trypanosome infection. Our work highlights a previously unrecognized role for PGRP-LA in maintaining gut barrier integrity and suggest that targeting this pathway could be a strategy to help reduce parasite transmission.

immunology↗

bioRxiv2025

Adeno-associated virus (AAV)-TBX18 does not generate biological pacemaker activity, unlike AAV-Hcn2

Gene therapy-based biological pacemakers have been proposed as an alternative to their hardware-based counterparts. In this context, short-term ectopic expression of the T-box transcription factor 18 (TBX18) in the ventricle reportedly generated potent short-term pacemaker function in various animal models. Here, we investigated the effect of adeno-associated virus (AAV)-mediated long-term expression of TBX18, and compared the outcome to that of the pacemaker ion channel Hcn2. Our findings revealed that CMV-driven ectopic TBX18 expression in mouse hearts led to severe cardiac fibrosis. At lower, non-fibrogenic levels, TBX18 maintained its transcriptional function but failed to induce pacemaker phenotypes. TBX18-expressing cells showed suppressed expression of key working myocardial genes, but the pacemaker gene program was not induced. Electrophysiological studies showed abnormal automaticity in TBX18-expressing cells, combined with prolonged repolarization and various current changes. However, no hyperpolarization-activated funny current was detected. In a complete AV-block rat model, AAV-mediated Hcn2 expression induced robust ectopic pacemaker activity in the presence of isoproterenol, whereas TBX18 expression neither generated such activities, nor augmented Hcn2-mediated pacing. In conclusion, at functional non-fibrogenic levels, TBX18 is neither sufficient nor necessary to induce pacemaker activity. In contrast, Hcn2 generates reliable pacing, making it a more viable candidate for biological pacemaker development.

physiology↗

bioRxiv2025

Scaling Personalized TMS: A Scalp-Based MRI-guided Alternative to Neuronavigation

BackgroundPersonalized transcranial magnetic stimulation (TMS) has shown promise in treating psychiatric and neurological disorders, but its accessibility is limited by reliance on costly and complex neuronavigation systems, particularly in resource-constrained clinical settings. ObjectiveTo develop and validate a scalp-based alternative to neuronavigation for personalized TMS targeting. MethodsWe developed a Continuous Proportional Coordinate (CPC) system-based approach for personalized TMS targeting and validated its performance through three operators across ten participants, using individualized DLPFC-SGC targets as an example. The validation framework included targeting consistency assessment, reproducibility evaluation, and cross-cortical generalizability analysis. ResultsThe CPC-based approach demonstrated comparable performance to neuronavigation, achieving 99.4% of its electric field strength (74.80 vs. 75.14 V/m; r = 0.962) and 93.9% of DLPFC-SGC functional connectivity (-0.216 vs. -0.230; r = 0.949), with high inter-operator reliability (ICC [≥] 0.903). Reproducibility analysis showed strong correlation between sessions (r = 0.948-0.957) with high reliability. Further simulations across 1,125 uniformly distributed cortical targets supported generalizability of this approach, with stable electric field preservation (99.07 {+/-} 1.54%) across different brain regions. ConclusionsThe CPC-based approach offers a practical alternative to neuronavigation, maintaining targeting accuracy and providing a more accessible option for personalized TMS implementation.

neuroscience↗

bioRxiv2025

Design, Optimization and Development of RIPK1 Degraders with Improved Pharmacokinetic and Pharmacodynamic Properties

The pivotal role of receptor-interacting protein kinase 1 (RIPK1) as a scaffold protein in mediating tumor resistance to immune checkpoint inhibitors (ICBs) underscores the significance of pharmacological RIPK1 degradation as a therapeutic strategy to enhance antitumor immunity. In this study, we present the design, synthesis, and evaluation of a novel series of RIPK1 degraders, derived from the optimization of the previously identified compound LD4172. Through systematic refinement of the linker, exit vector of the RIPK1 warhead, and the VHL ligand portion, we identified compound LD5097 (24b), which exhibited potent RIPK1 degradation activity across various cancer cell lines, with DC50 values of single digit nanomolar range and inducing more than 95% maximum degradation. Remarkably, LD5097 (24b) induced rapid and complete degradation of RIPK1 within 2 hours of treatment and enhanced TNF-mediated apoptosis in Jurkat cells. Furthermore, proteomic profiling unveiled the high selectivity of LD5097 (24b) in degrading RIPK1. LD5097 (24b) exhibited excellent metabolic stability and pharmacokinetic properties, characterized by low clearance, an extended half-life, and high plasma drug concentrations. Notably, a single administration of LD5097 (24b) effectively reduced RIPK1 protein levels in Jurkat xenograft tumor tissues in mice at both 6- and 24-hour post-administration. These findings underscore LD5097 (24b) as a promising RIPK1 degrader candidate, offering potent activity, favorable pharmaco-kinetic profiles, and notable pharmacodynamic effects, thereby holding significant promise in cancer immunology therapies.

pharmacology and toxicology↗

bioRxiv2025

A low-cost and open-source olfactometer to precisely deliver single odours and odour mixtures

Despite its profound influence on human emotion and memory, and its critical importance in animal behaviour, olfaction has historically been understudied compared to other sensory modalities. Contributing to this relative neglect may be challenges inherent to odour delivery: unlike visual or auditory stimuli, odorants must be vaporised, transported, and actively cleared, requiring specialised equipment and creating temporal delays and contamination risks. While commercial olfactometers provide reliable solutions, they can be expensive and, due to proprietary software, may be difficult to customise. Existing custom designs, though excellent, often require specialized technical skills and/or access to engineering workshops. Thus, to help widen access to well-controlled odour delivery, we developed a low-cost, fully open-source olfactometer that can be assembled without specialised facilities or engineering skills and customised according to experimental needs. Our design prioritises affordability, accessibility, and versatility while maintaining temporal precision and stimulus control across applications from rodent behaviour to human psychophysics. This methods articles provides full design specifications, assembly details, and behavioural validation across both rodents and humans with the aim of reducing barriers and enabling more laboratories to study this crucial sensory system.

neuroscience↗

bioRxiv2025

Enteric ChAT-expressing neurons as new target for Lactobacillus plantarum ameliorates inflammatory bowel diseases

The gut microbiota plays a crucial role in inflammatory bowel diseases (IBD), yet how specific microbial components influence disease progression remains incompletely understood. Our study reveals that decreased abundance of Lactobacillus species correlates with ulcerative colitis severity in patients. Among tested strains, L. plantarum A736, isolated from traditional fermented foods, demonstrated remarkable efficacy in ameliorating dextran sulfate sodium (DSS)-induced colitis in a mouse model. Strikingly, multi-omics analysis revealed that L. plantarum A736 uniquely enhances choline acetyltransferase-expressing (ChAT+) neurons in the enteric nervous system and elevates acetylcholine (ACh) levels. Further analysis identified that L. plantarum A736 metabolizes tryptophan to produce indole-3-lactic acid (ILA), and supplementation with ILA significantly mimics this strains anti-inflammatory effects by activating ChAT+ neurons. Crucially, selective ablation of colonic ChAT+ neurons completely abolished the therapeutic benefits of both L. plantarum A736 and ILA, establishing their essential role in mediating these effects. These findings demonstrate for the first time that microbial metabolites can directly modulate enteric neuronal circuits to regulate gut immunity. The identified ILA-ChAT+ neuron axis represents a novel neuro-immune pathway that could be targeted for IBD treatment. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/673902v1_ufig1.gif" ALT="Figure 1"> View larger version (63K): org.highwire.dtl.DTLVardef@1e0d3c5org.highwire.dtl.DTLVardef@16f5481org.highwire.dtl.DTLVardef@152283org.highwire.dtl.DTLVardef@18cfad0_HPS_FORMAT_FIGEXP M_FIG C_FIG

microbiology↗

bioRxiv2025

Unified Protein-Small Molecule Graph Neural Networks for Binding Site Prediction

Predicting small molecule binding sites on proteins remains a key challenge in structure-based drug discovery. While AlphaFold3 has transformed protein structure prediction, accurate identification of functional sites such as ligand binding pockets remains a distinct and unresolved problem. Graph neural networks have emerged as promising tools for this task, but most current approaches focus on local structural features and are trained on relatively small datasets, limiting their ability to model long-range protein-ligand interactions. Here, we develop YuelPocket, a new graph neural network that addresses these limitations through an innovative global graph design featuring a virtual joint node connecting all protein residues and small molecule atoms to capture long-range interactions while maintaining linear computational complexity. Trained on the comprehensive MOAD dataset containing over 38,000 protein-small molecule complexes, YuelPocket achieves exceptional performance with AUC-ROC values of 0.85 and 0.89 on COACH420 and Holo4k datasets, respectively.

bioinformatics↗

bioRxiv2025

Crosslinking of Lipid Nanoparticles Enhances the Delivery Efficiency and Efficacy of mRNA Vaccines

Lipid nanoparticles (LNPs) have enabled the effective delivery of RNA therapeutics and mRNA vaccines. However, their broader applications are limited by the suboptimal stability and endosomal escape efficiency. Here, we present an easy-to-adopt post-assembly crosslinking approach to enhance the structural and functional stability of mRNA LNPs. By leveraging a series of cholesterol derivatives and crosslinking methods, we induce crosslinks of the lipid components following mRNA LNP assembly to form the crosslinked LNPs (cLNPs). We systematically evaluated crosslinking parameters and identified optimal conditions that enhance both the physical stability and transfection efficiency of cLNPs. Our findings demonstrate that cLNPs exhibit improved structural integrity under storage and lyophilization conditions, as well as increased extracellular stability and endosomal escape efficiency, resulting in improved performance of mRNA LNPs both in vitro and in vivo. This crosslinking strategy represents a critical advance in LNP engineering, enabling more resilient LNPs and broadening the applicability of LNP-based therapies for gene therapy and vaccine delivery. Our work lays the foundation for developing next-generation LNPs with superior stability and delivery efficiency, broadening the impact of RNA therapeutics and vaccines.

bioengineering↗

bioRxiv2025

Erucamide regulates retinal neurovascular crosstalk

Neurovasculoglial crosstalk is critical in establishing and maintaining a functional neurovascular unit. Breakdown in the unit is central to many neurodegenerative disorders of the CNS of which the retina is a component. A growing literature indicated that primary fatty acid amides (PFAMs) can regulate this crosstalk between vasculature and neuronal tissues. In this study we describe a central role for erucamide, a 22:1 mono-unsaturated omega-9 fatty acid amide, in degenerating retinal tissues. Using high-resolution global mass spectrometry-based metabolomics, we cataloged metabolites in murine models of retinal degeneration and show that while PFAMs, in general, are highly dysregulated, erucamide is the one most significantly diminished during photoreceptor atrophy. Using rodent models of retinal degeneration and novel organosilane-modified porous silicon nanoparticles (pSiNPs) for the in vivo delivery of erucamide, we demonstrate that erucamide activates CD11b+ myeloid cells, leading to the upregulation of angiogenic and neurotrophic cytokines that stabilize retinal degeneration. We identified TMEM19 as a novel binding protein for erucamide that is crucial for human iPSC-derived macrophage precursor cells activation and subsequent neurotrophic and angiogenic factor production. These findings reveal a previously unknown PFAM pathway that is modulated during retinal degenerative diseases, demonstrating that erucamide or functional analogues and their action through TMEM19 may be useful as a therapeutic alternative to neuroprotective and stem cell-based approaches for the treatment of retinal degenerative diseases.

neuroscience↗

bioRxiv2025

Real-time in vivo imaging of rodent brain response to hypoperfusion enabled by remotely controlled elastomeric micro-balloons

Current preclinical models of ischemic stroke in mice do not permit simultaneous and continuous in vivo brain imaging during the peri-stroke period, therefore missing critical pathophysiological events that could be pivotal for stroke management at the early stage. Here we report remote control of the blood flow of cerebral arteries in live mice continuously at different states to induce stroke in a precise, reliable, and reversible manner. The sub-millimeter scale micro-balloons can expand more than four times their initial diameter, featuring a monolithic elastomeric wall with selectively stiffened regions for controlled inflation and elasticity depending on the target vessels. By allowing for the control of common carotid artery diameter through a cuff pressing against the artery, the micro-balloon recapitulates clinically relevant haemodynamics in a mouse model of global brain ischemia, evidenced by real-time imaging of the brain through intravital microscopy and magnetic resonance imaging. The presented micro-balloons hold significant potential to improve the treatment of stroke patients for minimally invasive intervention and in vivo imaging of the pathophysiological events in the peri-stroke phase.

bioengineering↗