{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:00:04Z","timestamp":1785214804704,"version":"3.55.0"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T00:00:00Z","timestamp":1785196800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    Resistance to tyrosine kinase inhibitors (TKIs) is a core limitation in the clinical treatment of chronic myeloid leukemia (CML). Although ponatinib can cover the T315I mutation, its clinical application is limited by severe adverse reactions at high doses. On the basis of the USP28-BCR-ABL-IFITM3 resistance signaling axis first identified in our previous study, a ginger-derived lipid carrier-mediated targeted nanodelivery system (IP@GLPs@\u03b5F) was constructed, which codelivers CRISPR\/Cas9-mediated IFITM3 knockout (IFITM3 KO) plasmid and ponatinib, establishing a new synergistic intervention mode of gene editing and targeted chemotherapy. When modified with \u03b5-polylysine and fucoidan via layer-by-layer self-assembly technology, the carrier has an average particle size of 226.1\u00a0nm, a drug encapsulation efficiency of 84.2%, and excellent biocompatibility.\n                    <jats:italic>In vitro<\/jats:italic>\n                    experiments confirmed that the optimal ratio (2.5\u00a0\u03bcg IFITM3-sg3 + 5\u00a0\u03bcM ponatinib) significantly reversed the drug resistance of K562R\u00a0cells, promoted apoptosis and inhibited proliferation.\n                    <jats:italic>In vivo<\/jats:italic>\n                    experiments using ectopic and orthotopic xenograft models verified that this system can efficiently target tumor tissues and significantly suppress the progression and metastasis of drug-resistant tumors, with no obvious toxic side effects on major organs. Mechanistically, this study revealed that IFITM3 mediates CML resistance by interacting with HSPA9 to activate the MET\/AKT\/BCL2 pathway and that IFITM3 KO can block this pathway and exert a synergistic antiresistance effect with ponatinib. This research provides a novel IFITM3-targeted synergistic therapeutic strategy and technical support for the clinical treatment of CML resistance.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1852978","type":"journal-article","created":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T04:26:16Z","timestamp":1785212776000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Targeted nanoparticle-mediated Co-delivery of IFITM3 KO and ponatinib reverses TKI resistance in chronic myeloid leukemia"],"prefix":"10.3389","volume":"17","author":[{"given":"Zhenyang","family":"Feng","sequence":"first","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaofang","family":"Ma","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Hu","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kexin","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Yang","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiyuan","family":"Wu","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiatian","family":"Lou","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruoyuan","family":"Shi","sequence":"additional","affiliation":[{"name":"Clinical Medical College, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kejia","family":"Xu","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wanlin","family":"Yang","sequence":"additional","affiliation":[{"name":"Kangda College, Nanjing Medical University","place":["Lianyungang, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Li","sequence":"additional","affiliation":[{"name":"Huzhou Municipal Hospital of Traditional Chinese Medicine","place":["Huzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Linglan","family":"Tu","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liyan","family":"Cheng","sequence":"additional","affiliation":[{"name":"School of Laboratory Medicine and Bioengineering, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]},{"name":"Zhejiang Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine, Hangzhou Medical College","place":["Hangzhou, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,7,28]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e86322","DOI":"10.7759\/cureus.86322","article-title":"Mechanisms of resistance to tyrosine kinase inhibitors in myeloid leukemias","volume":"17","author":"Alekrish","year":"2025","journal-title":"Cureus"},{"key":"B2","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1186\/s12964-023-01363-2","article-title":"Overcoming BCR::ABL1 dependent and independent survival mechanisms in chronic myeloid leukemia using a multi-kinase targeting approach","volume":"21","author":"Busch","year":"2023","journal-title":"Cell Commun. 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