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Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors

ABSTRACT: In vivo delivery systems (IDS) are designed to protect and transport therapeutics, but their efficacy is limited by low delivery efficiency. Here, we reveal that intestinal microbiota critically modulates IDS delivery efficiency by promoting hepatic clearance, whereas disrupting host-microbe interactions markedly enhances drug and gene delivery. Mechanistically, intestinal epithelial sensing of microbial stimuli triggers serotonin production that activates Kupffer cells. Transient inhibition of serotonin signaling, via receptor blockade or dietary intervention, attenuates hepatic clearance and improves systemic delivery. This strategy enhances the efficacy of IDS-based chemotherapy and oncolytic virotherapy and enables body-wide improvements in somatic genome editing and mRNA-based protein replacement. Together, these findings uncover a gut-liver immune axis that broadly constrains IDS performance, offering general approaches to improving in vivo therapeutic delivery.

ORGANISM(S): Mus musculus

PROVIDER: GSE315035 | GEO | 2025/12/30

REPOSITORIES: GEO

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Project description:Replicating viruses have broad applications in biomedicine, notably in cancer virotherapy and in the design of attenuated vaccines, however uncontrolled virus replication in vulnerable tissues can give pathology and often restricts the use of potent strains. Increased knowledge of tissue-selective microRNA expression now affords the possibility of engineering replicating viruses that are attenuated at the RNA level in sites of potential pathology, but retain wild type replication activity at sites not expressing the relevant microRNA. To assess the usefulness of this approach for the DNA virus, adenovirus, we have engineered a hepatocyte-safe wild type adenovirus 5 (Ad5), which normally mediates significant toxicity and is potentially lethal in mice. To do this we have included binding sites for hepatocyte-selective microRNA122a within the 3' UTR of the E1A transcription cassette. Imaging versions of these viruses, produced by fusing E1A with luciferase, showed that inclusion of microRNA122a binding sites caused up to 80 fold decreased hepatic expression of E1A following intravenous delivery to mice. Animals administered a ten-times lethal dose of wild type Ad5 (5 x 1010 viral particles/mouse) showed substantial hepatic genome replication and extensive liver pathology, while inclusion of 4 microRNA binding sites decreased replication 50-fold and virtually abrogated liver toxicity. This modified wild type virus retained full activity within cancer cells and provides a potent, liver-safe oncolytic virus. In addition to providing many potent new viruses for cancer virotherapy, microRNA-control of virus replication should provide a new strategy for designing safe attenuated vaccines applied across a broad range of viral diseases. four groups which we had were: WT: RNA extracted from livers of mice treated with wild type Ad5, 3 Replicates miR: RNA extracted from livers of mice treated with wild type Ad5 bearing mir122-binding sites in the 3'UTR of E1A (3 Replicates) Luc: RNA extracted from livers of mice treated with non-replicating Ad5 (3 Replicates) PBS: RNA extracted from livers of mice treated with PBS only (3 Replicates)

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Commensal-driven serotonin production modulates in vivo delivery of synthetic and viral vectors

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