Dual-aptamer-decorated reduction-activated dimeric-prodrug nanoparticles for broad-spectrum treatment of leukemia

Leukemia remains a fatal disease for most affected patients, and a simple and effective therapeutic strategy is urgently needed. Targeted delivery chemo-drugs to leukemia cells shows promise, but the diverse subtypes of leukemia make single-ligand nanomedicine often ineffective. Herein, a dual-aptamer decorated, reduction-responsive dimeric prodrug-based nanoparticle (NP), termed SXP-NPs, was developed using the two leukemia-specific aptamers Sgc8c and XQ-2d, a reduction-responsive podophyllotoxin (POD) dimeric prodrug, and DSPE-PEG2000. Because the receptors of XQ-2d (CD71) and Sgc8c (PTK7) are overexpressed in different subtypes of leukemia cells, SXP-NPs can broadly and selectively recognize these leukemia cells after intravenous administration, subsequently releasing POD in response to the intracellular high-reduction environment to kill the leukemia cells. In vitro experiments showed that these simple SXP-NPs can specifically bind to various leukemia cancer cells and kill them. In vivo experiments revealed that SXP-NPs can remarkably reduce spleen weight, decrease white blood cell counts, and extend overall survival in a preclinical leukemia animal model. The in vitro and in vivo validation demonstrated that SXP-NPs offer several advantages, including high drug-loading potential, broad-spectrum recognition of leukemia cells, reduced systemic toxicity, and enhanced therapeutic effects of the drug. Taken together, this study provides a simple and effective strategy for broad-spectrum leukemia therapy and highlights the clinical potential of SXP-NPs. • A dual-aptamer-decorated reduction-activated POD dimeric-prodrug NPs was designed and prepared. • SXP-NPs can broadly and specifically recognize leukemia cells. • In responsive intracellular high GSH, SXP-NPs can release active POD and kill leukemia cells. • SXP-NPs have the potential for broadly and highly efficiently eliminating leukemia.