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

  • Sci Adv. 2025 Mar 28;11(13):eado3923. doi: 10.1126/sciadv.ado3923.
Shilin Xu  1 ,  Tao Wang  1 ,  Xuechun Hu  1 ,  Hong Deng  1  2 ,  Yiyi Zhang  1  2 ,  Lei Xu  3 ,  Yang Zeng  3 ,  Jia Yu  4 ,  Weiqi Zhang  1  2 ,  Lin Wang  4 ,  Haiyan Xu  1
Affiliations
  • 1. Department of Biomedical Engineering, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, PR China.
  • 2. State Key Laboratory of Complex Severe and Rare Diseases, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100005, PR China.
  • 3. Institute of Hematology, Fifth Medical Center of Chinese PLA General Hospital, Beijing, PR China.
  • 4. State Key Laboratory of Common Mechanism Research for Major Disease, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
PMID: 40153509 DOI: 10.1126/sciadv.ado3923
Abstract

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.

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