Dendritic-cell-targeting virus-like particles as potent mRNA vaccine carriers.

Messenger RNA vaccines lack specificity for dendritic cells (DCs)-the most effective cells at antigen presentation. Here we report the design and performance of a DC-targeting virus-like particle pseudotyped with an engineered Sindbis-virus glycoprotein that recognizes a surface protein on DCs, and packaging mRNA encoding for the Spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or for the glycoproteins B and D of herpes simplex virus 1. Injection of the DC-targeting SARS-CoV-2 mRNA vaccine in the footpad of mice led to substantially higher and durable antigen-specific immunoglobulin-G titres and cellular immune responses than untargeted virus-like particles and lipid-nanoparticle formulations. The vaccines also protected the mice from infection with SARS-CoV-2 or with herpes simplex virus 1. Virus-like particles with preferential uptake by DCs may facilitate the development of potent prophylactic and therapeutic vaccines.

Identification of restrictive molecules involved in oncolytic virotherapy using genome-wide CRISPR screening.

Oncolytic viruses (OVs) offer a novel approach to treat solid tumors; however, their efficacy is frequently suboptimal due to various limiting factors. To address this challenge, we engineered an OV containing targets for neuron-specific microRNA-124 and Granulocyte-macrophage colony-stimulating factor (GM-CSF), significantly enhancing its neuronal safety while minimally compromising its replication capacity. Moreover, we identified PARP1 as an HSV-1 replication restriction factor using genome-wide CRISPR screening. In models of glioblastoma (GBM) and triple-negative breast cancer (TNBC), we showed that the combination of OV and a PARP inhibitor (PARPi) exhibited superior efficacy compared to either monotherapy. Additionally, single-cell RNA sequencing (scRNA-seq) revealed that this combination therapy sensitized TNBC to immune checkpoint blockade, and the incorporation of an immune checkpoint inhibitor (ICI) further increased the survival rate of tumor-bearing mice. The combination of PARPi and ICI synergistically enhanced the ability of OV to establish durable tumor-specific immune responses. Our study effectively overcomes the inherent limitations of OV therapy, providing valuable insights for the clinical treatment of TNBC, GBM, and other malignancies.

Cellular hnRNPAB binding to viral nucleoprotein inhibits flu virus replication by blocking nuclear export of viral mRNA.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) play critical roles in the nuclear export, splicing, and sensing of RNA. However, the role of heterogeneous nuclear ribonucleoprotein A/B (hnRNPAB) is poorly understood. In this study, we report that hnRNPAB cooperates with nucleoprotein (NP) to restrict viral mRNA nuclear export via inhibiting viral mRNA binding to ALY and NXF1. HnRNPAB restricts mRNA transfer from ALY to NXF1, inhibiting the mRNA nuclear export. Moreover, when cells are invaded by influenza A virus, NP interacts with hnRNPAB and interrupts the ALY-UAP56 interaction, leading to repression of ALY-viral mRNA binding, and then inhibits the viral mRNA binding to NXF1, leading to nuclear stimulation of viral mRNA. Collectively, these observations provide a new role of hnRNPAB to act as an mRNA nuclear retention factor, which is also effective for viral mRNA of influenza A virus, and NP cooperates with hnRNPAB to further restrict the viral mRNA nuclear export.