{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,25]],"date-time":"2026-09-25T09:47:01Z","timestamp":1790329621413,"version":"4.1.0"},"reference-count":0,"publisher":"National Academy of Sciences","issue":"25","license":[{"start":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T00:00:00Z","timestamp":1686614400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"HHS | National Institutes of Health","doi-asserted-by":"publisher","award":["DP2 TR002776"],"award-info":[{"award-number":["DP2 TR002776"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2023,6,20]]},"abstract":"<jats:p>Multiple myeloma (MM), a hematologic malignancy that preferentially colonizes the bone marrow, remains incurable with a survival rate of 3 to 6 mo for those with advanced disease despite great efforts to develop effective therapies. Thus, there is an urgent clinical need for innovative and more effective MM therapeutics. Insights suggest that endothelial cells within the bone marrow microenvironment play a critical role. Specifically, cyclophilin A (CyPA), a homing factor secreted by bone marrow endothelial cells (BMECs), is critical to MM homing, progression, survival, and chemotherapeutic resistance. Thus, inhibition of CyPA provides a potential strategy to simultaneously inhibit MM progression and sensitize MM to chemotherapeutics, improving therapeutic response. However, inhibiting factors from the bone marrow endothelium remains challenging due to delivery barriers. Here, we utilize both RNA interference (RNAi) and lipid\u2013polymer nanoparticles to engineer a potential MM therapy, which targets CyPA within blood vessels of the bone marrow. We used combinatorial chemistry and high-throughput in vivo screening methods to engineer a nanoparticle platform for small interfering RNA (siRNA) delivery to bone marrow endothelium. We demonstrate that our strategy inhibits CyPA in BMECs, preventing MM cell extravasation in vitro. Finally, we show that siRNA-based silencing of CyPA in a murine xenograft model of MM, either alone or in combination with the Food and Drug Administration (FDA)-approved MM therapeutic bortezomib, reduces tumor burden and extends survival. This nanoparticle platform may provide a broadly enabling technology to deliver nucleic acid therapeutics to other malignancies that home to bone marrow.<\/jats:p>","DOI":"10.1073\/pnas.2215711120","type":"journal-article","created":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T13:39:43Z","timestamp":1686663583000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":52,"title":["In vivo bone marrow microenvironment siRNA delivery using lipid\u2013polymer nanoparticles for multiple myeloma therapy"],"prefix":"10.1073","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4534-2779","authenticated-orcid":false,"given":"Pedro P. G.","family":"Guimar\u00e3es","sequence":"first","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Physiology and Biophysics, Institute of Biological Sciences, Universidade Federal de Minas Gerais, Belo Horizonte, MG 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2700-7678","authenticated-orcid":false,"given":"Christian G.","family":"Figueroa-Espada","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel S.","family":"Riley","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Department of Biomedical Engineering, Rowan University, Glassboro, NJ 08028"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ningqiang","family":"Gong","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5719-1336","authenticated-orcid":false,"given":"Lulu","family":"Xue","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4603-8517","authenticated-orcid":false,"given":"Tomasz","family":"Sewastianik","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"},{"name":"Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw 02776, Poland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter S.","family":"Dennis","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Loebel","sequence":"additional","affiliation":[{"name":"Department of Materials Science &amp; Engineering, University of Michigan, North Campus Research Complex, Ann Arbor, MI 48109"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda","family":"Chung","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah J.","family":"Shepherd","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7322-7829","authenticated-orcid":false,"given":"Rebecca M.","family":"Haley","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9810-5630","authenticated-orcid":false,"given":"Alex G.","family":"Hamilton","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5855-233X","authenticated-orcid":false,"given":"Rakan","family":"El-Mayta","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, Temple University, Philadelphia, PA 19122"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4255-0492","authenticated-orcid":false,"given":"Robert","family":"Langer","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel G.","family":"Anderson","sequence":"additional","affiliation":[{"name":"David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA 02142"},{"name":"Harvard and MIT Division of Health Science and Technology, Massachusetts Institute of Technology, Cambridge, MA 02142"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6849-1852","authenticated-orcid":false,"given":"Ruben D.","family":"Carrasco","sequence":"additional","affiliation":[{"name":"Department of Oncologic Pathology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215"},{"name":"Department of Pathology, Brigham &amp; Women\u2019s Hospital, Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3628-2244","authenticated-orcid":false,"given":"Michael J.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Department of Bioengineering, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"},{"name":"Institute for Regenerative Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2023,6,13]]},"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2215711120","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,13]],"date-time":"2023-06-13T13:39:49Z","timestamp":1686663589000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2215711120"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,13]]},"references-count":0,"journal-issue":{"issue":"25","published-print":{"date-parts":[[2023,6,20]]}},"alternative-id":["10.1073\/pnas.2215711120"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2215711120","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,13]]},"assertion":[{"value":"2022-09-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-03-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2023-06-13","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2215711120"}}