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At least 19 recordsLinked to original sources
PubMed2024

Directed evolution of engineered virus-like particles with improved production and transduction efficiencies.

Engineered virus-like particles (eVLPs) are promising vehicles for transient delivery of proteins and RNAs, including gene editing agents. We report a system for the laboratory evolution of eVLPs that enables the discovery of eVLP variants with improved properties. The system uses barcoded guide RNAs loaded within DNA-free eVLP-packaged cargos to uniquely label each eVLP variant in a library, enabling the identification of desired variants following selections for desired properties. We applied this system to mutate and select eVLP capsids with improved eVLP production properties or transduction efficiencies in human cells. By combining beneficial capsid mutations, we developed fifth-generation (v5) eVLPs, which exhibit a 2-4-fold increase in cultured mammalian cell delivery potency compared to previous-best v4 eVLPs. Analyses of v5 eVLPs suggest that these capsid mutations optimize packaging and delivery of desired ribonucleoprotein cargos rather than native viral genomes and substantially alter eVLP capsid structure. These findings suggest the potential of barcoded eVLP evolution to support the development of improved eVLPs.

Humans↗
PubMed2026

Live-cell transcriptomics with engineered virus-like particles.

Transcriptomic profiling is widely applied to characterize cellular gene expression, yet existing approaches lyse cells and preclude direct analysis of transcriptional dynamics in the same sample over time. We addressed this limitation by engineering mammalian cells to "self-report" their transcriptional states via mRNA export in virus-like particles (VLPs). Repeated sampling of culture media from VLP-producing cell populations faithfully captured evolving transcriptional states in complex biological settings, including acute inflammatory stimulation of primary cell spheroids and multi-day differentiation of pluripotent stem cells. We engineered VLP components for multiplexed readouts from distinct cell types in co-culture and for tuning self-reported RNA profiles. Finally, we demonstrated the unique utility of self-reporting for selective longitudinal tracking of endothelial cell dynamics within the enclosed architecture of a microphysiological co-culture system to identify perivascular stroma-dependent temporal gene programs underlying vasculogenesis. Altogether, this work establishes cellular self-reporting as a broadly enabling technology for live-cell transcriptome-wide gene expression profiling.

RNA↗
PubMed2025

Delivery of genome editors with engineered virus-like particles.

Genome editing technologies have revolutionized biomedical sciences and biotechnology. However, their delivery in vivo remains one of the major obstacles for clinical translation. Here, we introduce various emerging genome editing systems and review different delivery systems have been developed to realize the promise of in vivo gene editing therapies. In particular, we focus on virus-like particles (VLPs), an emerging delivery platform and provide in depth analysis on recent advancements to improve VLPs delivery potential and highlight opportunities for future improvements. To this end, we also provide detail workflows for engineered VLP (eVLP) selection, production, and purification, along with methods for characterization and validation.

Gene Editing↗
PubMed2025

Transcription- and Replication-Competent Virus-like Particle Systems for Marburg Virus.

Here, we describe the transcription- and replication-competent virus-like particle (trVLP) system for Marburg virus (MARV), which recapitulates transcription and replication of the viral genome in addition to viral particle assembly, egress, and entry. This protocol includes instructions for transfections for producer and acceptor cells and the use of trVLPs for infection.

Marburgvirus↗
PubMed1975

Pleomorphic virus-like particles in human faeces.

Pleomorphic fringed particles bearing some resemblance to orthomyxoviruses and coronaviruses were seen in 90 percent of stools from south Indian children and adults but not in stools from neonates. This finding may be related to the abnormalities of intestinal structure and function common in this region of India.

Adult↗
PubMed2025

Engineered virus-like particle-assembled Vegfa-targeting Cas9 ribonucleoprotein treatment alleviates neovascularization in wet age-related macular degeneration.

BACKGROUND: Age-related macular degeneration, particularly the wet form, is a leading cause of vision loss, characterized by vascular endothelial growth factor A (VEGFA) overproduction. Engineered virus-like particles (eVLPs) combine the efficiency of viral systems with the transient nature of non-viral platforms to offer a potential solution for delivering VEGFA-targeting genome editing enzymes in a safe and efficient manner. Here, we investigate the therapeutic efficacy of eVLPs for transient delivery of Vegfa-targeting Cas9 ribonucleoprotein in a laser-induced choroidal neovascularization mouse model of wet age-related macular degeneration. RESULTS: We find that Cas9-eVLPs enables efficient intracellular delivery in vitro, achieving up to 99% insertion and deletion frequency at Vegfa target locus and significant VEGFA protein downregulation in NIH/3T3 cells. A single subretinal injection of Cas9-eVLPs into the mouse retinal pigment epithelium effectively disrupts Vegfa expression, achieving an average indel efficiency of 16.7%. Compared to control groups, the laser-induced choroidal neovascularization mouse model exhibits significantly reduced choroidal neovascularization formation following Cas9-eVLPs intervention, and decreased VEGFA protein levels are detected in the retinal pigment epithelium. Furthermore, the retinal anatomical and functional toxicity are not affected after treatment. CONCLUSIONS: eVLPs exhibit the potential as a safe and efficient delivery platform for Cas9 ribonucleoproteins, achieving precise Vegfa downregulation and significant reduction in choroidal neovascularization in a mouse model of wet age-related macular degeneration. With transient delivery of gene editing enzymes, high editing efficiency, and minimal risk of genomic integration, eVLPs present a promising alternative to conventional delivery systems for advancing genome editing therapies in retinal diseases.

CRISPR-Associated Protein 9↗
PubMed2026

The present and future of nonviral delivery-based genome editing for hereditary hearing loss.

PURPOSE OF REVIEW: This review summarizes nonviral genome-editing delivery platforms for hereditary hearing loss, focusing on lipid nanoparticles (LNPs) and engineered virus-like particles (eVLPs), and discusses their advantages over adeno-associated virus-based delivery, as well as the barriers to clinical translation. RECENT FINDINGS: Recent advances have established LNPs as a clinically advanced nonviral platform, although challenges related to inner ear biodistribution, cell type specificity, endosomal escape, and immunogenicity remain to be addressed. In parallel, eVLPs have undergone substantial technical evolution, progressing from early low efficiency systems to advanced base editor- and prime editor-eVLP architectures that enhance cargo loading and editing efficiency. Extracellular vesicle-based genome editing has also emerged as an additional platform, although issues related to reproducibility, loading efficiency, and scalability remain major hurdles. SUMMARY: Nonviral genome editing platforms expand the therapeutic toolkit for hereditary hearing loss by enabling transient delivery of genome editors with potential safety advantages. Future efforts should focus on characterizing biodistribution and immunogenicity, refining cell type-specific tropism, and establishing scalable manufacturing processes to enable successful clinical translation.

Humans↗
PubMed2022

Therapeutic in vivo delivery of gene editing agents.

In vivo gene editing therapies offer the potential to treat the root causes of many genetic diseases. Realizing the promise of therapeutic in vivo gene editing requires the ability to safely and efficiently deliver gene editing agents to relevant organs and tissues in vivo. Here, we review current delivery technologies that have been used to enable therapeutic in vivo gene editing, including viral vectors, lipid nanoparticles, and virus-like particles. Since no single delivery modality is likely to be appropriate for every possible application, we compare the benefits and drawbacks of each method and highlight opportunities for future improvements.

CRISPR-Cas Systems↗
PubMed2025

Tofacitinib Mitigates the Increased SARS-CoV-2 Infection Susceptibility Caused by an IBD Risk Variant in the PTPN2 Gene.

BACKGROUND & AIMS: Coronavirus disease (COVID-19), caused by severe acquired respiratory syndrome-Coronavirus-2 (SARS-CoV-2), triggered a global pandemic with severe medical and socioeconomic consequences. Although fatality rates are higher among the elderly and those with underlying comorbidities, host factors that promote susceptibility to SARS-CoV-2 infection and severe disease are poorly understood. Although individuals with certain autoimmune/inflammatory disorders show increased susceptibility to viral infections, there is incomplete knowledge of SARS-CoV-2 susceptibility in these diseases. The aim of our study was to investigate whether the autoimmunity risk gene, PTPN2, which also confers elevated risk to develop inflammatory bowel disease, affects susceptibility to SARS-CoV-2 viral uptake. METHODS: Using samples from PTPN2 genotyped patients with inflammatory bowel disease, PTPN2-deficient mice, and human intestinal and lung epithelial cell lines, we investigated how PTPN2 affects expression of the SARS-CoV-2 receptor angiotensin converting enzyme 2 (ACE2), and uptake of virus-like particles expressing the SARS-CoV2 spike protein and live SARS-CoV-2 virus. RESULTS: We report that the autoimmune PTPN2 loss-of-function risk variant rs1893217 promotes expression of the SARS-CoV-2 receptor, ACE2, and increases cellular entry of SARS-CoV-2 spike protein and live virus. Elevated ACE2 expression and viral entry were mediated by increased Janus kinase-signal transducers and activators of transcription signaling and were reversed by the Janus kinase inhibitor, tofacitinib. CONCLUSION: Collectively, our findings uncover a novel risk biomarker for increased expression of the SARS-CoV-2 receptor and viral entry, and identify a clinically approved therapeutic agent to mitigate this risk.

Humans↗
PubMed2026

Identification and characterization of anti-chikungunya virus compounds using a biosafe toolkit.

Chikungunya virus (CHIKV) is a re-emerging mosquito-borne alphavirus for which no specific antiviral therapy is currently available. During the large outbreak in Foshan, Guangdong Province, China, in July 2025, CHIKV rapidly spread to neighboring regions and caused more than 16,000 confirmed cases. In this study, the predominant outbreak strain of CHIKV was selected as the reference sequence to establish a panel of complementary biosafe tools for antiviral compound screening and mechanistic investigation. A virus replicon particle (VRP) system for CHIKV was first constructed and applied to compound library screening, resulting in the identification of three candidate antiviral compounds: MDL-12330A, bazedoxifene acetate, and anidulafungin. To further validate their antiviral activities and investigate their potential mechanisms, CHIKV functional evaluation systems were subsequently established, including vesicular stomatitis virus (VSV)- and murine leukemia virus (MLV)-based pseudovirus systems for viral entry, a replicon RNA system for post-entry replication-associated processes, a replication-defective nsP4 mutant replicon RNA system for primary translation, and a virus-like particle (VLP) system for viral particle assembly and budding assessment. Using these complementary systems, we systematically evaluated the antiviral profiles of the three candidate compounds across multiple stages of the CHIKV life cycle. This analysis revealed distinct stage-specific inhibitory patterns and provided insights into their potential antiviral mechanisms, which warrant validation using authentic CHIKV infection to assess their translational potential.

Chikungunya virus↗
PubMed2026

Host-virus dynamics in anaerobic digesters facing abiotic inhibition.

Viruses play a major role in controlling the structure and dynamics of microbial communities in anaerobic digesters, ecosystems sensitive to disturbances that inhibit methane production. Here, we studied the interplay between abiotic disturbances, microbiome and virome composition, and process performance, to assess whether provirus induction can be triggered by abiotic stresses known to inhibit anaerobic digestion (ammonium, phenol and sodium chloride). We monitored viral dynamics in batch mesophilic anaerobic digesters fed with biowaste through shotgun metavirome sequencing. The diversity of both prokaryotes and viruses was high, with Clostridiales dominating the prokaryotic community and Caudoviricetes dominating the viromes. We identified 132 viral contigs and 19 host genera that were differentially abundant under disturbed conditions. No significant impact of the tested abiotic stresses on provirus induction was observed under the current experimental and analytical framework. The results were consistent with viruses exerting steady, background-level predation through a putative combination of kill-the-winner dynamics at the sub-genus level and piggyback-the-winner dynamics, rather than stress-triggered, synchronous lytic bursts. A few auxiliary metabolic genes were detected, potentially targeting carbon, sulfur and cofactor metabolism in anaerobic digestion. Temperate viruses were dominant, representing up to 71% of the viral genomes confirmed as complete across all conditions. Electron microscopy analysis revealed diverse virus-like particles, including head-tailed particles typical of Caudoviricetes, but also spherical, rod-shaped and spindle-shaped particles typical of archaeal viruses. Notably, we present a new virus family, Eurekaviridae, of spindle-shaped viruses associated with methanogenic archaea.

Anaerobiosis↗
PubMed2026

Dengue and chikungunya vaccines past, present and future: implications for travelers.

PURPOSE OF REVIEW: Novel vaccines for dengue and chikungunya viruses offer new prevention options against two globally important arboviral diseases. This review summarizes recent developments in vaccine licensure, implementation, real-world experience and research priorities, with emphasis on implications for both endemic populations and travelers. RECENT FINDINGS: Of the three live-attenuated dengue vaccines licensed to date, TAK-003 is authorized in >40 countries and Butantan-DV in Brazil, while manufacturing of CYD-TDV is discontinued. Long-term and postmarketing data continue to refine understanding of serotype-specific protection, waning immunity, and rare adverse events.For chikungunya, two single-dose vaccines are licensed-a live-attenuated vaccine (VLA1553) and virus-like particle vaccine (PXVX0317). Uptake is guided by emerging safety and effectiveness data, with each platform offering potential advantages in different settings.Further data on long-term protection, safety, effectiveness, use in vulnerable populations and integration into outbreak management and immunization systems is anticipated. SUMMARY: Dengue and chikungunya vaccines are increasingly being used in immunization programs and pretravel consultations. Further real-world data are needed-particularly for seronegative dengue vaccine recipients and older, immunocompromised or medically at-risk adults. Research priorities include developing single-dose, nonlive dengue vaccines suitable for high-risk groups, understanding long-term chikungunya vaccine performance, and exploring broader flaviviral or pan-arboviral platforms.

Humans↗
PubMed2026

Maternal contact and age-dependent succession influence the assembly of the calf rumen microbiome and virome.

Early-life colonization of the rumen is particularly important; however, the processes by which microbial and viral communities are transmitted and developed remain poorly understood. Here, we present a genome-resolved investigation of the effects of maternal contact and age-dependent succession on the calf rumen microbiome and DNA virome by comparing calves raised with or without maternal contact across early life using the metagenome-assembled genomes (MAGs) and viral operational taxonomic units (vOTUs) reconstructed from whole- and virus-like particle metagenomes. Across longitudinal samples from calves and their mothers, we identified 694 MAGs and 30,479 vOTUs, substantially expanding current genome databases and revealing extensive microbial and viral novelty. Our analyses demonstrated that both prokaryotes and DNA viruses are shared between dams and calves, with greater sharing observed in calves raised with maternal contact than in calves raised without maternal contact. Notably, viral sharing between cow-calf pairs was markedly lower compared to prokaryotes, suggesting high turnover and rapid viral diversification. Age-associated analyses further revealed coordinated shifts in prokaryotes and their viruses, with dominant genera such as Prevotella, Ruminococcus, and Fibrobacter, and their corresponding viruses increasing after day 40. These findings indicate that the early-life rumen microbiome and DNA virome undergo substantial age-dependent succession and are associated with maternal contact, providing new insights into host-microbe-virus interactions during rumen development.IMPORTANCEThis study provides one of the first genome-resolved views of DNA viral community development during early rumen colonization in calves (from 1 week to 70 days of age) and reveals how maternal contact and age influence the establishment of the calf rumen microbiome and virome. By analyzing longitudinal samples from calves raised with or without their mothers, we show that prokaryotes and their viruses undergo coordinated, age-dependent succession. Our results demonstrate that maternal separation alters the assembly of the calf rumen microbiome, highlighting the influence of maternal contact during early-life rumen development. These findings underscore the high plasticity of the early-life rumen ecosystem and suggest that early management practices, such as maternal separation, can have lasting effects on rumen development. This work provides fundamental insights into the establishment and succession of the calf rumen microbiome and DNA virome during early life and may contribute to future microbiome manipulation studies.

Animals↗
PubMed2025

Design of nanobody targeting SARS-CoV-2 spike glycoprotein using CDR-grafting assisted by molecular simulation and machine learning.

The design of proteins capable effectively binding to specific protein targets is crucial for developing therapies, diagnostics, and vaccine candidates for viral infections. Here, we introduce a complementarity-determining region (CDR) grafting approach for designing nanobodies (Nbs) that target specific epitopes, with the aid of computer simulation and machine learning. As a proof-of-concept, we designed, evaluated, and characterized a high-affinity Nb against the spike protein of SARS-CoV-2, the causative agent of the COVID-19 pandemic. The designed Nb, referred to as Nb Ab.2, was synthesized and displayed high-affinity for both the purified receptor-binding domain protein and to the virus-like particle, demonstrating affinities of 9 nM and 60 nM, respectively, as measured with microscale thermophoresis. Circular dichroism showed the designed protein's structural integrity and its proper folding, whereas molecular dynamics simulations provided insights into the internal dynamics of Nb Ab.2. This study shows that our computational pipeline can be used to efficiently design high-affinity Nbs with diagnostic and prophylactic potential, which can be tailored to tackle different viral targets.

Spike Glycoprotein, Coronavirus↗