Overcoming chemoresistance in acute myeloid leukemia via co-delivery of siGLUT1 and hydroxycamptothecin using hyaluronic acid-conjugated nanocarriers

Multi-drug resistance (MDR) presents a major challenge in the treatment of acute myeloid leukemia (AML). Combining chemotherapy and gene therapy offers a promising strategy to improve drug sensitivity in resistant AML cells. However, designing an effective delivery system for co-administration of multiple agents while maintaining biosafety remains challenging. In this study, we developed a biocompatible co-delivery system that incorporates hydroxycamptothecin (HCPT) and glucose transporter 1 (GLUT1) small interfering RNA (siRNA). HCPT was loaded onto gold nanoparticles through crystallization, ensuring drug stability and safety. The branched configuration of self-branched chitosan contributed to improved gene delivery efficiency. The hyaluronic acid-conjugated nanocarrier specifically targeted CD44 receptors expressed on AML cells, while the pH-sensitive properties of self-branched chitosan promoted localized drug and gene release. This system effectively delivered the therapeutic agents to tumor sites, improving cellular uptake and synergistically inhibiting DNA synthesis by downregulating glycolysis and P-glycoprotein expression in leukemic cells. Both in vitro and in vivo experiments demonstrated strong antitumor efficacy and excellent biosafety. This co-delivery system offers a promising strategy for overcoming drug resistance in AML and holds potential for clinical translation.