A DNA Nanomachine Modulates the Stemness-Associated Signaling Pathways for Overcoming Chemoresistance by Temporally Programming Drug Release

Chemoresistance is a primary cause of cancer treatment failure, due to the lack of specific regulatory strategies arising from unclear mechanisms. Here, we uncover the pivotal role of the PRMT1/SOX2 axis in regulating cancer stemness, a key factor contributing to cancer chemoresistance. In light of this, we construct a DNA nanomachine (DNM) to overcome chemoresistance by reversing cancer stemness. This DNM is constructed using a programmable DNA origami framework, incorporating CD44-targeting aptamers and glutathione (GSH)-responsive stemness inhibitors (DCLX069) as functional components. The DNM exhibits a specific affinity toward CD44-overexpressing tumor cells, enabling the effective delivery of the loaded cisplatin (CDDP) to the tumor cells. Upon entering the tumor cells, DCLX069 is rapidly released from the DNM due to high intracellular GSH levels, leading to swift regulation of the PRMT1/SOX2 axis. In contrast, CDDP exhibits a gradual enzymatic release profile. This temporally programmed release enables the reversal of cancer stemness before chemotherapy initiation, resulting in a substantial improvement in CDDP chemosensitivity and a significant increase in the median survival of tumor-bearing mice from 27 to over 56 d with DNM assistance. This study highlights the promising potential of this DNA nanotechnology-empowered therapy in addressing chemoresistance in malignant tumors.