Scholarlink

<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 <i>JAK2</i><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>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

USP5 inhibition via bone marrow-targeted engineered exosomes for myeloproliferative neoplasms therapy

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年7月11日

查看全文
  • Wenjun Wang,
  • Yufeng Jiang,
  • Donglei Zhang,
  • Xian Zhang,
  • Qian Liang,
  • Jun Shi,
  • Yuan Zhou,
  • Fuling Zhou

摘要

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.