{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,19]],"date-time":"2026-08-19T18:47:52Z","timestamp":1787165272791,"version":"build-2736575974"},"reference-count":68,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T00:00:00Z","timestamp":1685145600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006244","name":"KiKa","doi-asserted-by":"publisher","award":["329"],"award-info":[{"award-number":["329"]}],"id":[{"id":"10.13039\/501100006244","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>Lipid nanoparticles (LNPs) have evolved rapidly as promising delivery systems for oligonucleotides, including siRNAs. However, current clinical LNP formulations show high liver accumulation after systemic administration, which is unfavorable for the treatment of extrahepatic diseases, such as hematological disorders. Here we describe the specific targeting of LNPs to hematopoietic progenitor cells in the bone marrow. Functionalization of the LNPs with a modified Leu-Asp-Val tripeptide, a specific ligand for the very-late antigen 4 resulted in an improved uptake and functional siRNA delivery in patient-derived leukemia cells when compared to their non-targeted counterparts. Moreover, surface-modified LNPs displayed significantly improved bone-marrow accumulation and retention. These were associated with increased LNP uptake by immature hematopoietic progenitor cells, also suggesting similarly improved uptake by leukemic stem cells. In summary, we describe an LNP formulation that successfully targets the bone marrow including leukemic stem cells. Our results thereby support the further development of LNPs for targeted therapeutic interventions for leukemia and other hematological disorders.<\/jats:p>","DOI":"10.3390\/pharmaceutics15061603","type":"journal-article","created":{"date-parts":[[2023,5,27]],"date-time":"2023-05-27T16:10:53Z","timestamp":1685203853000},"page":"1603","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Increased Bone Marrow Uptake and Accumulation of Very-Late Antigen-4 Targeted Lipid Nanoparticles"],"prefix":"10.3390","volume":"15","author":[{"given":"Laura E.","family":"Swart","sequence":"first","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel H. A. M.","family":"Fens","sequence":"additional","affiliation":[{"name":"Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CG Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anita","family":"van Oort","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0133-9490","authenticated-orcid":false,"given":"Piotr","family":"Waranecki","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L. Daniel","family":"Mata Casimiro","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Tuk","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martijn","family":"Hendriksen","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"van den Brink","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Schweighart","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cor","family":"Seinen","sequence":"additional","affiliation":[{"name":"CDL Research, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryan","family":"Nelson","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1927-9286","authenticated-orcid":false,"given":"Anja","family":"Krippner-Heidenreich","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tom","family":"O\u2019Toole","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond M.","family":"Schiffelers","sequence":"additional","affiliation":[{"name":"CDL Research, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8893-9578","authenticated-orcid":false,"given":"Sander","family":"Kooijmans","sequence":"additional","affiliation":[{"name":"CDL Research, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5404-6483","authenticated-orcid":false,"given":"Olaf","family":"Heidenreich","sequence":"additional","affiliation":[{"name":"Princess M\u00e1xima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht, The Netherlands"},{"name":"Wolfson Childhood Cancer Research Centre, Newcastle University, Newcastle upon Tyne NE1 7RY, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/j.jconrel.2010.02.020","article-title":"Targeted delivery of SiRNA to CD33-positive tumor cells with liposomal carrier systems","volume":"144","author":"Rothdiener","year":"2010","journal-title":"J. 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