2. Academic Validation
  3. USP5 inhibition via bone marrow-targeted engineered exosomes for myeloproliferative neoplasms therapy

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

  • J Nanobiotechnology. 2025 Jul 11;23(1):501. doi: 10.1186/s12951-025-03588-4.
Wenjun Wang 1 2 3,  Yufeng Jiang 4,  Donglei Zhang 1,  Xian Zhang 1,  Qian Liang 2 3 5,  Jun Shi 6 7,  Yuan Zhou 8 9,  Fuling Zhou 10
Affiliations

Affiliations

  • 1 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China.
  • 2 State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China.
  • 3 Tianjin Institutes of Health Science, Tianjin, 301600, China.
  • 4 School of Information and Mathematics, Yangtze University, Jingzhou, Hubei, 434000, China.
  • 5 Zhoukou Central Hospital, Zhoukou, China.
  • 6 State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. shijun@ihcams.ac.cn.
  • 7 Tianjin Institutes of Health Science, Tianjin, 301600, China. shijun@ihcams.ac.cn.
  • 8 State Key Laboratory of Experimental Hematology, Haihe Laboratory of Cell Ecosystem, Institute of Hematology & Blood Diseases Hospital, National Clinical Research Center for Blood Diseases, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, 300020, China. yuanzhou@ihcams.ac.cn.
  • 9 Tianjin Institutes of Health Science, Tianjin, 301600, China. yuanzhou@ihcams.ac.cn.
  • 10 Department of Hematology, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, China. zhoufuling@whu.edu.cn.
PMID: 40646529 DOI: 10.1186/s12951-025-03588-4
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.

Keywords

Bone marrow targeting; Deubiquitinating enzyme; Mesenchymal stem cells; Myeloproliferative neoplasms.

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