Nanosynergist-engineered oncolytic adenovirus enhancing immune-virotherapy efficacy for glioblastoma via interrupting antiviral responses

Oncolytic adenoviruses (OA) are promising therapeutics for glioblastoma (GBM) due to their unique capability of selectively lysing tumor cells and activating the immune response. However, their therapeutic potential is often impeded by limited cellular internalization caused by low expression of OA receptors, as well as restricted OA proliferation due to antiviral responses. In this work, a novel type of OA, named nanosynergist-engineered OA (nsOA), was developed by functionalizing the viral surface with siRNA-loaded hyperbranched polymers. The nanosynergist not only enhanced the infectivity of OA but also augmented virus replication, ultimately potentiating their oncolysis efficacy. We revealed that the enhanced replication of the virus was initiated by the downregulation of signal transducer and activator of transcription-3, which suppressed the transcription of interferon-stimulated genes, ultimately circumventing the antiviral defense of tumor cells. Furthermore, the innate ability of OA to disrupt endosomal membranes was found to improve the endosomal escape of the nanosynergist, creating synergistic effect that amplified the therapeutic benefits. A single dose of nsOA markedly increased the production of progeny viruses and prolonged the survival of mice. Collectively, these results provide an effective and valuable strategy to engineer OA, which may lead to innovative immunotherapies for various cancers. [Display omitted] •This nanosynergist favorably strengthened OA replication via siRNA mediated interruption of STAT3 gene.•The downregulation of STAT3 effectively bypassed the antiviral defense of tumor cells by inhibiting ISGs expression.•OA disrupted the endosomal membranes and facilitated the escape of nanosynergist from endosomes.•A single dose of nsOA increased viral titer, enhanced OA-mediated therapy, and prolonged the survival of mice with glioma.