{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T10:27:52Z","timestamp":1789986472007,"version":"4.0.1"},"reference-count":61,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007923","name":"University of Wisconsin Carbone Cancer Center","doi-asserted-by":"publisher","award":["P30 CA014520"],"award-info":[{"award-number":["P30 CA014520"]}],"id":[{"id":"10.13039\/100007923","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006108","name":"National Center for Advancing Translational Sciences","doi-asserted-by":"publisher","award":["UL1 TR002373"],"award-info":[{"award-number":["UL1 TR002373"]}],"id":[{"id":"10.13039\/100006108","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100006058","name":"St. Baldrick's Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006058","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100015982","name":"Midwest Athletes Against Childhood Cancer","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100015982","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Osteosarcoma frequently metastasizes to the lungs, significantly reducing survival in pediatric and young adult patients, with current therapies having limited efficacy. This study aimed to develop an inhalable nanoemulsion formulation to enhance targeted pulmonary drug delivery and restore natural killer (NK) cell-mediated immunity against metastatic osteosarcoma.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      A nanoemulsion composed of medium-chain triglyceride (MCT) oil and Distearoyl-rac-glycerol-PEG\n                      <jats:sub>2000<\/jats:sub>\n                      (DSG-PEG2000), yielding droplets consistently smaller than 200 nm, was designed with demonstrated stability (&amp;gt;550 days), biocompatibility, mucus penetration ability, minimal toxicity on respiratory epithelium, and efficient cellular uptake. To enhance NK cell function in the osteosarcoma tumor microenvironment, the nanoemulsion was loaded with SIS3, a SMAD3 inhibitor targeting immunosuppressive TGF-\u03b2 signaling, and conjugated with a cysteine-modified form of the NK-cell killer immunoglobulin-like receptor (KIR) antagonist nonamer peptide VAPWNSDAL (VAP\u2013DAC) to block inhibitory LILRB1\/ILT-2 on NK-92 cells.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>The resulting SIS3-VAP\u2013DAC nanoemulsion maintained particle sizes below 162 nm, stability over one month, enhanced cytotoxicity of human NK-92 cells, and restoration of granzyme B secretion despite TGF-\u03b2 suppression, as well as induced NKG2D ligand expression on murine osteosarcoma cells. Intranasal administration of the SIS3-VAP\u2013DAC nanoemulsion effectively reduced pulmonary tumor burden in human osteosarcoma xenograft mouse models with no observable clinical toxicity.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>This study establishes a novel inhalable nanoemulsion platform that\u00a0significantly restores NK-cell functionality against pulmonary metastatic osteosarcoma.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1772375","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T06:51:18Z","timestamp":1770879078000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Development and evaluation of an inhalable nanoemulsion system for enhancing NK cell function against osteosarcoma pulmonary metastases"],"prefix":"10.3389","volume":"17","author":[{"given":"Sookyung","family":"Hwang","sequence":"first","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin School of Pharmacy","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul D.","family":"Bates","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vasiliki","family":"Valkanioti","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin School of Pharmacy","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chih-Chun","family":"Chang","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin School of Pharmacy","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandro","family":"Mecozzi","sequence":"additional","affiliation":[{"name":"Division of Pharmaceutical Sciences, University of Wisconsin School of Pharmacy","place":["Madison, WI, United States"]},{"name":"Department of Chemistry, University of Wisconsin-Madison","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M.","family":"Capitini","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]},{"name":"Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health","place":["Madison, WI, United States"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e28352","DOI":"10.1002\/pbc.28352","article-title":"Osteosarcoma","volume":"68","author":"Eaton","year":"2021","journal-title":"Pediatr Blood Cancer"},{"key":"B2","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1051\/sicotj\/2017028","article-title":"Osteosarcoma: a comprehensive review","volume":"4","author":"Misaghi","year":"2018","journal-title":"SICOT-J"},{"key":"B3","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/s41413-023-00246-z","article-title":"Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment","volume":"11","author":"Tian","year":"2023","journal-title":"Bone Res"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14020360","article-title":"Metastatic progression of osteosarcomas: A review of current knowledge of environmental versus oncogenic drivers","volume":"14","author":"Odri","year":"2022","journal-title":"Cancers"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbo.2019.100230","article-title":"Risk and clinicopathological features of osteosarcoma metastasis to the lung: A population-based study","volume":"16","author":"Huang","year":"2019","journal-title":"J Bone Oncol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.1039260","article-title":"The role of innate immune cells in the tumor microenvironment and research progress in anti-tumor therapy","volume":"13","author":"Lu","year":"2023","journal-title":"Front Immunol"},{"key":"B7","doi-asserted-by":"crossref","DOI":"10.1007\/978-3-030-43032-0_12","article-title":"Natural killer cell immunotherapy for osteosarcoma","volume-title":"Current advances in osteosarcoma. 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