USP5@Exosome-CP

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.