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To address this, a lipopolymer (PEI\u2010C) is developed by conjugating lipid to polyethylenimine and formulated lipopolymer nanoparticles (LPNPs) via complexation with siRNA. The siRNA delivery efficiency of LPNPs is evaluated in vitro in t(4;11)\u2010positive ALL cells (RS4;11 and SEM) as well as \u201cnormal\u201d peripheral blood mononuclear cells (PBMCs) from human donors and bone marrow stromal cells (BMSCs) from mice. Molecular effects are assessed by quantifying target mRNA silencing and downstream apoptosis. In vivo biodistribution and therapeutic efficacy are examined in mouse models. LPNPs demonstrated significantly higher siRNA uptake than commercial reagents in PBMCs and BMSCs, reaching siRNA uptakes of 87.2% and 93.0% in RS4;11 and SEM cells, respectively. Molecular analyses revealed effective silencing of KMT2A::AFF1 mRNA (\u224880% in RS4;11), accompanied by BCL2 downregulation and increased apoptosis. In vivo, LPNPs showed efficient siRNA biodistribution to leukemia\u2010associated organs (spleen and bone marrow) and significantly reduced leukemia burden in a systemic RS4;11 xenograft mouse model and improved survival. These findings suggest that PEI\u2010C\u2010formulated LPNPs present a promising avenue for therapeutic siRNA delivery in ALL, effectively targeting leukemia\u2010associated organs, and warrant further exploration in clinical studies.<\/jats:p>","DOI":"10.1002\/adhm.202502019","type":"journal-article","created":{"date-parts":[[2025,7,21]],"date-time":"2025-07-21T07:26:17Z","timestamp":1753082777000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Suppressing t(4;11) Acute Leukemia by Lipopolymer Nanoparticle Delivery of siRNA Targeting\n                    <i>KMT2A::AFF1<\/i>\n                    with Enhanced Extrahepatic Delivery"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1346-355X","authenticated-orcid":false,"given":"Mohammad","family":"Nasrullah","sequence":"first","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton AB T6G 2H1 Canada"},{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remant","family":"KC","sequence":"additional","affiliation":[{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amarnath Praphakar","family":"Rajendran","sequence":"additional","affiliation":[{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saba Abbasi","family":"Dezfouli","sequence":"additional","affiliation":[{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cezary","family":"Kucharski","sequence":"additional","affiliation":[{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics Terry Fox Laboratory British Columbia Cancer Research Institute University of British Columbia  Vancouver BC V6T 1Z3 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0119-732X","authenticated-orcid":false,"given":"Spencer B.","family":"Gibson","sequence":"additional","affiliation":[{"name":"Department of Oncology Faculty of Medicine &amp; Dentistry University of Alberta  Edmonton AB T6G 1Z2 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Brandwein","sequence":"additional","affiliation":[{"name":"Division of Hematology Department of Medicine Faculty of Medicine &amp; Dentistry University of Alberta Edmonton AB T6G 2B7 Canada"}],"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 Maxima Center for Pediatric Oncology  Utrecht CS 3584 The Netherlands"},{"name":"Wolfson Childhood Cancer Research Centre Newcastle University  Newcastle upon Tyne NE1 7RU UK"},{"name":"Department of Hematology University of Utrecht Medical Center  Utrecht CX 3584 The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1118-4170","authenticated-orcid":false,"given":"Hasan","family":"Uludag\u0306","sequence":"additional","affiliation":[{"name":"Faculty of Pharmacy and Pharmaceutical Sciences University of Alberta  Edmonton AB T6G 2H1 Canada"},{"name":"Department of Chemical and Materials Engineering Faculty of Engineering University of Alberta  Edmonton AB T6G 1R1 Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,21]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02368-7"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-023-05812-3"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02261-3"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021005736"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11030821"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1182\/blood.2022017645"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1182\/bloodadvances.2021004580"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-024-02164-3"},{"key":"e_1_2_9_9_1","unstructured":"\u201cFDA approves revumenib for relapsed or refractory acute leukemia with a KMT2A translocation | FDA \u201d can be found underhttps:\/\/www.fda.gov\/drugs\/resources\u2010information\u2010approved\u2010drugs\/fda\u2010approves\u2010revumenib\u2010relapsed\u2010or\u2010refractory\u2010acute\u2010leukemia\u2010kmt2a\u2010translocation(access April 2025)."},{"key":"e_1_2_9_10_1","first-page":"3488","volume":"109","author":"Stein E. 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