Biology subjects

Lehto, V.-P.

Publications and source records attributed to Lehto, V.-P..

5 recordsLinked to original sources

bioRxiv2026

Mechanical Activation of Piezo1 by Virus-like Nanospikes to Potentiate STING-driven Macrophage Reprogramming

Mechanotransduction plays a fundamental role in regulating immune cell function, yet how engineered virus-like nanospikes engage mechanosensitive signaling pathways to modulate innate immunity remains poorly understood. Here, we report virus-like nanotopography as a previously unrecognized regulator of Piezo1-mediated mechanotransduction in macrophages using virus-like mesoporous silica nanoparticles (VLPSi) with tunable rigid nanospike lengths. We demonstrate a direct structure-activity relationship between nanospike geometry and Piezo1-dependent Ca{superscript 2}+ influx, with longer nanospikes inducing significantly greater intracellular Ca{superscript 2}+ signaling. Building on this mechanistic insight, we developed biomimetic cancer cell membrane (CM)-coated, MSA-2-loaded VLPSi nanoparticle (CM/MSA-2@VLPSi) and investigate the combination of nanospikes-activated Piezo1 with STING signaling and CM antigens presentation in macrophage immune reprogramming. The resulting biomimetic nanoparticles robustly activate the STING-TBK1-IRF3/NF-{kappa}B axis, increase IFN-{beta} and pro-inflammatory cytokine production, and promote macrophage polarization toward M1 phenotype in a spike-length-dependent manner. Collectively, the present study provides a biomimetic strategy for enhancing the M1 polarization of macrophage through the coordinated regulation of mechanical, inflammatory, and antigenic signals.

immunology↗

bioRxiv2026

Bioinspired Virus-Like Porous Silica Amplify Lipid-Mediated mRNA Delivery

Lipid nanoparticles (LNPs) have demonstrated strong potential in COVID-19 mRNA vaccines nevertheless they still face the challenges in low mRNA delivery efficacy. Virus-like porous silica (VLPSi) nanoparticles (NPs) represent a promising biomimetic delivery platform because their spiked morphology may enhance cellular internalization and promote endosomal membrane disruption. However, the application of VLPSi for mRNA has been rarely explored. In this study, hybrid lipid-VLPSi NPs were developed by combining VLPSi with either lipoplexes (LPs) or LNPs. The effects of lipid types, mass ratio of different compositions, and amine modifications of VLPSi on mRNA delivery were studied. The results demonstrated that both LP and LNP could be successfully integrated with VLPSi to form hybrid delivery systems for mRNA transfection. VLPSi could significantly enhance mRNA delivery of both LPs and LNPs due to improved cellular uptake, structural stabilization of the mRNA complex, and enhanced endosomal escape mediated by the rigid virus-like surface architecture. Among the tested lipid formulations, the ionizable lipid ALC-0315 and helper lipid DOPE with mass ratio of 5:3 was the most effective lipid composition to be integrated with VLPSi, showing the highest mRNA delivery performance. In addition, amino modification of VLPSi was found to be a critical factor for efficient mRNA delivery. Hybrid LNPs containing amino-modified VLPSi showed significantly higher transfection efficiency than those containing unmodified VLPSi. Notably, amino-modified LNP-VLPSi achieved up to fivefold higher gene expression than conventional LNPs. Overall, this study establishes VLPSi as an efficient platform for amplifying lipid-mediated mRNA delivery. Owing to its straightforward integration into widely used LNP systems, VLPSi offers an adaptable and effective strategy for advancing next-generation mRNA therapeutics.

bioengineering↗

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

Biomimetic virus-like mesoporous silica nanoparticles activate NK cells indirectly via monocyte crosstalk

Cancer immunotherapies show clinical promise but often rely on T-cell priming and are limited by tumor heterogeneity and the immunosuppressive tumor microenvironment (TME). Innate immune activation offers a complementary strategy, with specific aim in natural killer (NK) cell activation for antigen-independent response. Biomimetic nanoparticles combining virus-like morphology with cell membrane (CM) coating offer a strategy to engage this innate immune axis. This study investigates virus-like mesoporous silica nanoparticles (VLPSi) with tunable spikes, surface functionalization, and CM coating as innate immunity modulators. Optimization revealed that longer spikes, amine functionalization, and CM coating synergistically enhance NK cell activation within human PBMCs, as indicated by CD69/CD25 upregulation and IFN-{gamma} secretion. CD14+ monocyte depletion attenuated activation, identifying monocyte-dependent crosstalk as a key mechanism. In purified NK cells, engineered CM-coated VLPSi induced early activation and supported feeder-free expansion. These results define topology, surface chemistry, and CM coating as parameters for innate immune modulation. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=69 SRC="FIGDIR/small/720074v1_ufig1.gif" ALT="Figure 1"> View larger version (18K): org.highwire.dtl.DTLVardef@db5cdorg.highwire.dtl.DTLVardef@1ab41eorg.highwire.dtl.DTLVardef@127428dorg.highwire.dtl.DTLVardef@82609a_HPS_FORMAT_FIGEXP M_FIG C_FIG

immunology↗

bioRxiv2024

Biomimetic porous silicon for rationally engineered combination therapy to induce immunogenic cell death

Combined chemo-photothermal therapy (CHT-PTT) is a promising treatment for metastatic cancers. It enables the synergistic induction of immunogenic cell death (ICD), while sensitising suppressive tumour microenvironment to immunotherapy. To induce ICD, the rational design of a combined CHT-PTT regimen remains unclear. In the present study, black porous silicon nanoparticles (BPSi NPs) were utilized as both drug carriers and photothermal conversion agents. To enhance their colloidal stability and homotypic targeting, BPSi NP surfaces were modified with polyethylene glycol and further coated with cancer cell membranes (CMs). Six chemotherapeutic drugs with different cell growth inhibition mechanisms were tested against metastatic MDA-MB-231 breast cancer cells to evaluate their ICD induction potentials. Finally, in the combined CHT-PTT, the effect of temperature was evaluated. Based on the analysis of ICD markers, high-mobility group box 1 and calreticulin proteins, we found that bromodomain-containing protein 4 inhibitor, (+)-JQ-1 (JQ1) was the optimal drug, and the mild-hyperthermia temperature of 45 {degrees}C was the best temperature setting in the combined CHT-PTT to induce ICD. Thus, our study provides rationally designed CHT-PTT regimen for efficient cancer treatment with high efficacy and low side effects.

bioengineering↗