{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,31]],"date-time":"2026-07-31T15:59:48Z","timestamp":1785513588953,"version":"3.56.0"},"reference-count":33,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"funder":[{"name":"Division of Intramural Research","award":["HL155450"],"award-info":[{"award-number":["HL155450"]}]},{"name":"Division of Intramural Research","award":["HL166241"],"award-info":[{"award-number":["HL166241"]}]},{"name":"Division of Intramural Research","award":["HL1855251"],"award-info":[{"award-number":["HL1855251"]}]},{"name":"Wake Forest Clinical and Translational Science Award","award":["UL1-TR001420"],"award-info":[{"award-number":["UL1-TR001420"]}]},{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"crossref","award":["P40-OD010965"],"award-info":[{"award-number":["P40-OD010965"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The Council to Advance Human Health","award":["2023-102"],"award-info":[{"award-number":["2023-102"]}]}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Human Gene Therapy"],"abstract":"<jats:p>\n                    Adeno-associated virus (AAV) gene therapy is frequently hindered by dose-limiting toxicities and preexisting neutralizing antibodies (nAbs). Here, we evaluate enhancer polymer (ePL), a cargo-less poly(L-lactic-co-glycolic acid) nanoparticle, the systemic administration of which demonstrated biocompatibility in nonhuman primates (NHPs) and generated a protransduction serum secretome that significantly enhanced AAV uptake in human iPSC-derived cardiomyocytes. Proteomic analysis of human peripheral blood mononuclear cell-derived secretomes identified a transient upregulation of AAV-entry factors, including ITGB3, alongside a downregulation of inflammatory cytokine pathways. Mechanistically, ePL-stimulated macrophages release a paracrine secretome that triggers the rapid, transient degradation of hepatic insulin receptor substrate 2 and subsequent AKT inhibition in liver and isolated primary mouse hepatocytes. Additionally, ePL attenuated the levels of NHP-derived nAbs\n                    <jats:italic toggle=\"yes\">in vitro<\/jats:italic>\n                    and in a mouse-NHP xenotransfusion model without depleting total systemic immunoglobulins. Finally, ePL reduced Immunoglobulin G (IgG) secretory capacity of splenic B cells, suggesting a mechanistic link by which levels of nAbs are likely attenuated. Together, these findings highlight ePL as a promising supporting agent to improve AAV gene transfer, warranting its further optimization for clinical translation.\n                  <\/jats:p>","DOI":"10.1177\/10430342261471124","type":"journal-article","created":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T04:19:57Z","timestamp":1785385197000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["A Modular Polymer Enhancer Promotes AAV Transduction and Circumvents Preexisting Immunity in Nonhuman Primates"],"prefix":"10.1177","author":[{"given":"Lauren E.","family":"Switala","sequence":"first","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Department of Biomedical Engineering, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Cardiovascular Research Institute, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6045-6200","authenticated-orcid":false,"given":"Afsana Mim","family":"Khandaker","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Cardiovascular Research Institute, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Department of Pharmacology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sumita","family":"Dutta","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Cardiovascular Research Institute, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew J.","family":"Jorgensen","sequence":"additional","affiliation":[{"name":"Comparative Medicine, Pathology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8830-1809","authenticated-orcid":false,"given":"Andrei","family":"Maiseyeu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Department of Biomedical Engineering, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Cardiovascular Research Institute, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"The Blood, Heart, Lung, and Immunology Research Center, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, USA"},{"name":"Department of Pharmacology, Case Western Reserve University School of Medicine and University Hospitals, Cleveland, Ohio, 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