Biology subjects

Leinonen, H.

Publications and source records attributed to Leinonen, H..

6 recordsLinked to original sources

bioRxiv2026

Tunable Rigid Spikes on Virus-Like Porous Silica Enable Mechanistically Controlled Nanovaccine Platforms

Virus-like particles represent an emerging and promising vaccine platform. However, these particles are inherently mechanically soft and have limited control over particle surface architecture, thereby constraining their immunological control. Herein, we report the rational design of bioinspired virus-like porous silica (VLPSi) nanoparticles (NPs) with tunable and mechanically rigid spike architectures that function dually as antigen delivery carriers and immune adjuvants. Using ovalbumin (OVA) as a model antigen, we systematically elucidate the spiky structure-function relationship in antigen delivery and immune response. VLPSi NPs exhibit good biocompatibility, sustained antigen release, and markedly enhanced cellular uptake and endosomal escape compared with soft spike and spherical counterparts. Mechanistic investigations combining molecular dynamics simulations and proteomic analyses reveal that rigid spike architectures reduce the energetic barrier for cellular internalization and concurrently activate dual pathways involving endosomal Toll like receptors and calcium signaling. Consequently, VLPSi with long spikes elicit significantly enhanced humoral and cellular immune responses, outperforming the particles with shorter spikes, spherical shape as well as clinically used alum adjuvant. To demonstrate translational potential, bioinspired antibacterial vaccines were produced by loading Staphylococcus aureus surface protein rEsxB. The VLPSi-based vaccine elicited robust protective immunity to achieve complete (100%) survival following lethal challenge without detectable adverse effects, whereas traditional Alum-adjuvanted formulation conferred only minimal protection, with a survival rate of 10%. Collectively, this work establishes VLPSi with tunable spikes as a mechanistically controlled platform for next generation vaccines. Graphic Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=145 SRC="FIGDIR/small/720861v1_ufig1.gif" ALT="Figure 1"> View larger version (47K): org.highwire.dtl.DTLVardef@1f6c13eorg.highwire.dtl.DTLVardef@1090d07org.highwire.dtl.DTLVardef@1364926org.highwire.dtl.DTLVardef@fc68ab_HPS_FORMAT_FIGEXP M_FIG C_FIG

bioengineering↗

bioRxiv2026

Dyrk1a gene dosage controls bipolar cell development and retinal connectivity.

Mammalian retina development is governed by a core set of eye-field transcription factors that orchestrate tissue lamination and neuronal connectivity through tightly regulated genetic hierarchies. The LIM homeodomain gene Lhx2 functions as a master eye-field regulator and this study identifies Dyrk1a as a previously unrecognised effector of Lhx2-dependent programs during mouse retinal development. Conditional deletion of Dyrk1a in retinal progenitor cells led to increased apoptosis within the inner retina demonstrating a requirement for Dyrk1a in cell survival and lineage maintenance. Adult heterozygous mice exhibited dorsoventral reductions in bipolar cell number and indicated a gene-dosage-sensitive control of interneuron survival. Bipolar cell loss disrupted their mosaic organisation and resulted in diminished activity across both scotopic and photopic retinal pathways. Dyrk1a haploinsufficient mice also displayed pronounced disruption of inner plexiform layer stratification consistent with defective laminar targeting and synaptic partner integration. This study defines a gene-dosage-dependent mechanism through which transcriptional hierarchies regulate neuronal connectivity and function during mammalian retinal development.

developmental biology↗

bioRxiv2025

Novel Cln8 p.R24G mouse line replicates major clinical features of Northern epilepsy

RationaleNorthern epilepsy belongs to a group of genetically diverse lysosomal storage diseases, the neuronal ceroid lipofuscinoses (NCLs). A characteristic feature of NCL pathology is the accumulation of autofluorescent ceroid lipofuscin in the central nervous system. Northern epilepsy is a late-infantile-onset disease. Patients develop normally until 5-10 years old, when they first present with general tonic-clonic seizures, followed by progressive cognitive impairment and a decline in motor skills. Northern epilepsy is caused by a missense variant in CLN8, causing a p.R24G amino acid substitution. CLN8 deficiency has been studied traditionally using motor neuron degeneration (mnd) mice, which carry a spontaneous frame shift variant in the murine orthologue Cln8, which is not known to exist in humans. MethodsWe have generated the first Cln8 p.R24G mouse model (Cln8R24G) using CRISPR/Cas9. Phenotyping analysis of the mice was conducted using behavioral and histopathological studies focusing on the brain and retina. ResultsAt birth, Cln8R24G KI mice were viable and asymptomatic. As the mice aged, a progressive accumulation of autofluorescent ceroid lipofuscin containing the mitochondrial ATP synthase subunit C was evident in different brain regions and retinal layers. Health monitoring revealed that mutant mice developed progressive but mild motor symptoms around 7 months of age. Spontaneous epileptic seizures, like those observed in Northern epilepsy patients, were detected and recorded. An increase in FosB staining intensity, reflecting neuronal hyperactivity, was observed in hippocampal CA1-CA3 pyramidal and dentate granule cells and correlated well with the intensity of seizure activity. Neuroinflammation was evident at 4 months and increased dramatically with age, mainly in the thalamic VPN/VPL nuclei and moderately in the cortex. Neurodegeneration was most prominent in the VPN/VPL thalamic nuclei. ConclusionsWe have generated the Cln8R24G mouse model that genocopies, for the first time, the pathogenic CLN8 variant present in patients with Northern epilepsy. These mice phenocopy major clinical features of the human disease, including mild motor impairment and, unlike the mnd mice, spontaneous generalized tonic-clonic seizures. We hypothesize that our mouse model will open new possibilities for developing and testing targeted treatment options for Northern epilepsy and, more broadly, for early-onset neurodegenerative disorders associated with epilepsy.

neuroscience↗

bioRxiv2025

Female sex is a risk factor for exacerbated lipid peroxidation and disease in murine retinitis pigmentosa

Oxidative stress is an important aspect in retinal degenerations that could be targeted in various forms of currently untreatable diseases. It is generally believed that males are more predisposed to oxidative stress than females due to their higher metabolic activity and/or lower antioxidant capacity. However, studies using mouse disease models have demonstrated that photoreceptor degeneration progresses faster in females. Sex hormones likely play a role, but the cellular mechanism behind the sex difference is unclear. In the current study, we confirmed that the accelerated disease phenotype in female rd10 and P23H retinitis pigmentosa mice coincides with sexual maturity, and further, we found that it co-occurs with increased retinal lipid peroxidation. Instead, protein oxidation and inflammatory marker levels were similar between the sexes. Retinal lipid profiling revealed higher levels of polyunsaturated fatty acid (PUFA)-containing lipids in healthy 2-month-old female mice compared to males, whereas before puberty the sex difference in retinal PUFAs was absent. Analysis of open bulk retina transcriptomic data from middle-aged humans found supplemental evidence of sex-related differences in retinal energy metabolism pathways. Besides mechanistic study directed to reveal the reasons for differential lipid peroxidation between sexes, more research needs to be directed to study sex differences in retinal metabolism and lipid composition across animal species. The current results highlight the need to consider the impact of sex differences when undertaking preclinical experiments with RP models. Significance statementThis article suggests female sex as a significant risk factor for progressive photoreceptor degenerative disease, based on experiments in two widely used retinitis pigmentosa mouse models. The disease phenotype in females accelerates markedly after sexual maturity, especially in mice carrying the autosomal dominant P23H rhodopsin mutation. This acceleration is associated with intensified retinal lipid peroxidation. Given the retinas high energy demand, continuous photoreceptor cilia renewal, and constant light exposure that generates reactive oxygen species, the susceptibility of photoreceptor membranes to oxidative damage is substantial. Our findings suggest that retinal metabolism may differ between sexes after puberty, potentially influenced by sex hormones, which could contribute to the increased vulnerability of females to photoreceptor degenerative diseases.

physiology↗

bioRxiv2025

Mechanism of biomimetic virus-like nanoparticles in triggering immune response elucidated by proteomics

The use of biomimetic nanoparticles (NPs) with virus-like morphology have recently attracted research interest as novel delivery platforms and immune adjuvants. However, the exact interactions between the nanoparticles and immune cells as well as the mechanism involved are not known in detail. This motivated us to develop virus-like mesoporous silica nanoparticles (VLP) to characterize their physicochemical properties, and to determine the immune pathways induced by the particles in mouse macrophages. The results showed inclusion of spikes mimicking virion structures on the surface increased cellular uptake and enhanced immune response as compared to spherical NPs. Proteomic analysis revealed that the RIG-I-like receptor signaling pathway, Chemokine signaling pathway, MAPK signaling pathway, NF-{kappa}B signaling pathway, Toll-like receptor signaling pathway, B cell receptor signaling pathway and Th1 and Th2 cell differentiation pathways were involved in regulating the immune response when macrophages interacted with VLP. When the spikes increased from 5 to 30 nm, the expression levels of immune-related proteins including TRAF6 and PIAS4 proteins enhanced. This study revealed the interaction pathways and key proteins in the activation of immune response with VLP, which may provide insights to develop novel immunotherapy for enhanced efficacy. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=177 SRC="FIGDIR/small/640536v3_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@395d6forg.highwire.dtl.DTLVardef@25238dorg.highwire.dtl.DTLVardef@41001borg.highwire.dtl.DTLVardef@16dfe2e_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2020

Homeostatic plasticity triggered by rod photoreceptor degenerative disease is associated with maintenance of sensitive night vision

Neuronal plasticity of the inner retina has been observed in response to photoreceptor degeneration. Typically, this phenomenon has been considered maladaptive and may preclude vision restoration in the blind. However, several recent studies utilizing triggered photoreceptor ablation have shown adaptive responses in bipolar cell dendrites expected to support normal vision. Whether such homeostatic plasticity occurs during progressive photoreceptor degenerative disease to help maintain normal visual behavior is unknown. We addressed these issues in an established mouse model of Retinitis Pigmentosa caused by the P23H mutation in rhodopsin. We show robust modulation of the retinal transcriptomic network reminiscent of the neurodevelopmental state as well as potentiation of rod - rod bipolar cell signaling following rod photoreceptor degeneration. Additionally, we found highly sensitive night vision in P23H mice even when more than half of the rod photoreceptors were lost. The results implicate retinal adaptation leading to persistent visual function during photoreceptor degenerative disease.

neuroscience↗