{"title":"USP5 inhibition via bone marrow-targeted engineered exosomes for myeloproliferative neoplasms therapy.","authors":"Wenjun Wang, Yufeng Jiang, Donglei Zhang, Xian Zhang, Qian Liang, Jun Shi, Yuan Zhou, Fuling Zhou","doi":"10.1186/s12951-025-03588-4","DOIUrl":null,"url":null,"abstract":"<p><p>Myeloproliferative neoplasms (MPNs) are challenging to treat due to the complex bone marrow (BM) microenvironment and lack of curative therapies. Current treatments fail to eliminate malignant clones and face issues like drug resistance. This study addressed these challenges by identifying USP5 as a critical regulator in JAK2<sup>V617F</sup>-mutated mesenchymal stem cells (MSCs), which promotes proliferation by suppressing Caspase-3-mediated apoptosis. We developed engineered exosomes (USP5@Exosome-CP) co-expressing CXCR4 and a P-selectin-targeting peptide to enhance BM targeting. These exosomes, loaded with the USP5 inhibitor USP5-IN-1, demonstrated efficient BM homing and sustained drug release. In MPN mouse models, USP5@Exosome-CP significantly reduced MSC proliferation, extended survival, and showed minimal systemic toxicity. Transcriptomic analysis revealed that USP5 knockdown activated apoptosis pathways and suppressed oncogenic signaling. Our results establish USP5 as a therapeutic target and validate the engineered exosome platform as a promising strategy for MPN treatment, offering a blueprint for targeting other hematologic malignancies. This approach combines USP5 inhibition with BM-targeted nanotechnology, providing a proof-of-concept for personalized MPN therapy with improved efficacy and reduced off-target effects.</p>","PeriodicalId":16383,"journal":{"name":"Journal of Nanobiotechnology","volume":"23 1","pages":"501"},"PeriodicalIF":10.6000,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247442/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Nanobiotechnology","FirstCategoryId":"5","ListUrlMain":"https://doi.org/10.1186/s12951-025-03588-4","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Myeloproliferative neoplasms (MPNs) are challenging to treat due to the complex bone marrow (BM) microenvironment and lack of curative therapies. Current treatments fail to eliminate malignant clones and face issues like drug resistance. This study addressed these challenges by identifying USP5 as a critical regulator in JAK2V617F-mutated mesenchymal stem cells (MSCs), which promotes proliferation by suppressing Caspase-3-mediated apoptosis. We developed engineered exosomes (USP5@Exosome-CP) co-expressing CXCR4 and a P-selectin-targeting peptide to enhance BM targeting. These exosomes, loaded with the USP5 inhibitor USP5-IN-1, demonstrated efficient BM homing and sustained drug release. In MPN mouse models, USP5@Exosome-CP significantly reduced MSC proliferation, extended survival, and showed minimal systemic toxicity. Transcriptomic analysis revealed that USP5 knockdown activated apoptosis pathways and suppressed oncogenic signaling. Our results establish USP5 as a therapeutic target and validate the engineered exosome platform as a promising strategy for MPN treatment, offering a blueprint for targeting other hematologic malignancies. This approach combines USP5 inhibition with BM-targeted nanotechnology, providing a proof-of-concept for personalized MPN therapy with improved efficacy and reduced off-target effects.
骨髓增生性肿瘤(mpn)由于复杂的骨髓(BM)微环境和缺乏根治性治疗而具有挑战性。目前的治疗方法无法消除恶性克隆,并面临耐药性等问题。本研究通过确定USP5作为jak2v617f突变间充质干细胞(MSCs)的关键调节因子来解决这些挑战,USP5通过抑制caspase -3介导的凋亡来促进增殖。我们开发了工程外泌体(USP5@Exosome-CP),共表达CXCR4和p选择素靶向肽,以增强BM靶向。这些外泌体装载了USP5抑制剂USP5- in -1,显示出有效的BM归巢和持续的药物释放。在MPN小鼠模型中,USP5@Exosome-CP显著降低MSC增殖,延长生存期,并显示最小的全身毒性。转录组学分析显示,USP5敲低激活了凋亡途径,抑制了致癌信号传导。我们的研究结果确定了USP5作为治疗靶点,并验证了工程外泌体平台作为MPN治疗的一种有前景的策略,为靶向其他血液系统恶性肿瘤提供了蓝图。该方法将USP5抑制与靶向脑脊髓瘤的纳米技术相结合,为个性化MPN治疗提供了概念验证,提高了疗效,减少了脱靶效应。
期刊介绍:
Journal of Nanobiotechnology is an open access peer-reviewed journal communicating scientific and technological advances in the fields of medicine and biology, with an emphasis in their interface with nanoscale sciences. The journal provides biomedical scientists and the international biotechnology business community with the latest developments in the growing field of Nanobiotechnology.