A dual chemodrug-loaded hyaluronan nanogel for differentiation induction therapy of refractory AML via disrupting lysosomal homeostasis

作者：Shilin Xu, Tao Wang, Xuechun Hu, Hong Deng, Yiyi Zhang, Lei Xu, Yang Zeng, Jia Yu, Weiqi Zhang, Lin Wang, Haiyan Xu · 发表于：Science Advances · 年份：2025 · DOI：10.1126/sciadv.ado3923 · 被引用次数：19 · 研究领域：Acute Myeloid Leukemia Research、Hematopoietic Stem Cell Transplantation、Retinoids in leukemia and cellular processes

Relapsed/refractory acute myeloid leukemia (rrAML) is a malignant blood cancer with an extremely poor prognosis, largely ascribed to the drug-resistant leukemia stem cells (LSCs). Most patients suffer from a risk of difficult-to-cure as well as severe systemic toxicity when receiving standard chemotherapies. As hyaluronic acid (HA) is a specific ligand of CD44 highly expressed by LSCs, we had HA self-assembled with cisplatin and daunorubicin to form a dual chemodrug nanogel (HA/Cis/Dau) to afford the targeted therapeutic interventions of rrAML. HA/Cis/Dau displayed an extra therapeutic function of inducing the granulocyte-monocyte differentiation in CD44 + rrAML cells, an rrAML mouse model, and primary blasts isolated from patients with AML. Unlike free drugs directly diffusing and killing rrAML cells, HA/Cis/Dau transported the drugs into lysosomes, causing lysosomal membrane permeabilization, ROS accumulation, and thus a metabolic reprogramming of the rrAML cells. Moreover, HA/Cis/Dau was featured with alleviated side effects, ease of preparation, and cost effectiveness, therefore holding great promises for the targeted treatment of rrAML.