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

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.