Center for Stem Cell and Regenerative Medicine and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, China.
Liangzhu Laboratory, Zhejiang University, 1369 West Wenyi Road, Hangzhou, 311121, China.
Nat Commun. 2024 Jul 7;15(1):5689. doi: 10.1038/s41467-024-50021-9.
Leukemia is a kind of hematological malignancy originating from bone marrow, which provides essential signals for initiation, progression, and recurrence of leukemia. However, how to specifically deliver drugs to the bone marrow remains elusive. Here, we develop biomimetic vesicles by infusing hematopoietic stem and progenitor cell (HSPC) membrane with liposomes (HSPC liposomes), which migrate to the bone marrow of leukemic mice via hyaluronic acid-CD44 axis. Moreover, the biomimetic vesicles exhibit superior binding affinity to leukemia cells through intercellular cell adhesion molecule-1 (ICAM-1)/integrin β2 (ITGB2) interaction. Further experiments validate that the vesicles carrying chemotherapy drug cytarabine (Ara-C@HSPC-Lipo) markedly inhibit proliferation, induce apoptosis and differentiation of leukemia cells, and decrease number of leukemia stem cells. Mechanically, RNA-seq reveals that Ara-C@HSPC-Lipo treatment induces apoptosis and differentiation and inhibits the oncogenic pathways. Finally, we verify that HSPC liposomes are safe in mice. This study provides a method for targeting bone marrow and treating leukemia.
白血病是一种起源于骨髓的血液系统恶性肿瘤，为白血病的发生、进展和复发提供了必要的信号。然而，如何将药物特异性递送到骨髓仍然是一个难题。在这里，我们通过将脂质体注入造血干细胞和祖细胞（HSPC）膜中来开发仿生囊泡（HSPC 脂质体），这些囊泡通过透明质酸-CD44 轴迁移到白血病小鼠的骨髓中。此外，仿生囊泡通过细胞间黏附分子-1（ICAM-1）/整合素β2（ITGB2）相互作用表现出对白血病细胞的优异结合亲和力。进一步的实验验证了携带化疗药物阿糖胞苷（Ara-C@HSPC-Lipo）的囊泡可显著抑制白血病细胞的增殖，诱导其凋亡和分化，并减少白血病干细胞的数量。从机制上讲，RNA-seq 表明 Ara-C@HSPC-Lipo 处理诱导了细胞凋亡和分化，并抑制了致癌途径。最后，我们验证了 HSPC 脂质体在小鼠体内是安全的。本研究为靶向骨髓治疗白血病提供了一种方法。
