{"doi":"10.3389/fimmu.2023.1196453","title":"Extracellular Vesicles-mediated recombinant IL-10 protects against ascending infection-associated preterm birth by reducing fetal inflammatory response","abstract":"Background Fetal inflammatory response mediated by the influx of immune cells and activation of pro-inflammatory transcription factor NF-κB in feto-maternal uterine tissues is the major determinant of infection-associated preterm birth (PTB, live births < 37 weeks of gestation). Objective To reduce the incidence of PTB by minimizing inflammation, extracellular vesicles (EVs) were electroporetically engineered to contain anti-inflammatory cytokine interleukin (IL)-10 (eIL-10), and their efficacy was tested in an ascending model of infection (vaginal administration of E. coli ) induced PTB in mouse models. Study design EVs (size: 30-170 nm) derived from HEK293T cells were electroporated with recombinant IL-10 at 500 volts and 125 Ω, and 6 pulses to generate eIL-10. eIL-10 structural characters (electron microscopy, nanoparticle tracking analysis, ExoView [size and cargo content] and functional properties (co-treatment of macrophage cells with LPS and eIL-10) were assessed. To test efficacy, CD1 mice were vaginally inoculated with E. coli (10 10 CFU) and subsequently treated with either PBS, eIL-10 (500ng) or Gentamicin (10mg/kg) or a combination of eIL-10+gentamicin. Fetal inflammatory response in maternal and fetal tissues after the infection or treatment were conducted by suspension Cytometer Time of Flight (CyTOF) using a transgenic mouse model that express red fluorescent TdTomato (mT+) in fetal cells. Results Engineered EVs were structurally and functionally stable and showed reduced proinflammatory cytokine production from LPS challenged macrophage cells in vitro . Maternal administration of eIL-10 (10 µg/kg body weight) crossed feto-maternal barriers to delay E. coli -induced PTB to deliver live pups at term. Delay in PTB was associated with reduced feto-maternal uterine inflammation (immune cell infiltration and histologic chorioamnionitis, NF-κB activation, and proinflammatory cytokine production). Conclusions eIL-10 administration was safe, stable, specific, delayed PTB by over 72 hrs and delivered live pups. The delivery of drugs using EVs overcomes the limitations of in-utero fetal interventions. Protecting IL-10 in EVs eliminates the need for the amniotic administration of recombinant IL-10 for its efficacy.","journal":"Frontiers in Immunology","year":2023,"id":332066,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":26,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9639,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":745068,"name":"Angela Mosebarger","orcid":"0000-0003-4683-6359","position":1,"is_corresponding":false},{"id":441714,"name":"Enkhtuya Radnaa","orcid":"0000-0001-8142-8137","position":2,"is_corresponding":false},{"id":904824,"name":"Emma Rowlinson","orcid":"0000-0002-4545-0385","position":3,"is_corresponding":false},{"id":894641,"name":"Natasha Vora","orcid":null,"position":4,"is_corresponding":false},{"id":865424,"name":"Stephen J. Fortunato","orcid":null,"position":5,"is_corresponding":false},{"id":328586,"name":"Surendra Sharma","orcid":"0000-0002-4331-3467","position":6,"is_corresponding":false},{"id":1058062,"name":"Melody Safarzadeh","orcid":null,"position":7,"is_corresponding":false},{"id":78684,"name":"Ramkumar Menon","orcid":"0000-0001-9213-6105","position":8,"is_corresponding":false},{"id":299692,"name":"Ananth Kumar Kammala","orcid":"0000-0001-5300-2083","position":0,"is_corresponding":true}],"reference_count":125,"raw_metadata":null,"created_at":"2026-07-19T01:09:25.015646Z","pmid":"37600782","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}