A research team led by Professor Chao Zhang at Zhujiang Hospital, Southern Medical University, has introduced a new approach using DNA nanomachines to address chemoresistance in small cell lung cancer (SCLC). The group identified the PRMT1/SOX2 signaling axis as a central factor in chemotherapy resistance for this cancer type. Based on this finding, they developed a DNA nanomachine that delivers drugs in a controlled sequence to target resistant tumor cells.
The strategy involves the rapid release of a stemness inhibitor followed by the gradual delivery of cisplatin, a standard chemotherapy drug. This approach aims to reverse tumor stemness—a characteristic linked to self-renewal and differentiation—and improve sensitivity to chemotherapy.
Chemoresistance is one of the main reasons cancer treatments fail and is often associated with more aggressive disease and worse outcomes. It is influenced not only by how well drugs reach tumors but also by internal cellular pathways that control various aspects of tumor biology. Tumor stemness has been recognized as an important driver of both chemoresistance and recurrence, but the underlying mechanisms are not fully understood.
Professor Zhang’s team found that PRMT1 levels are significantly higher in chemoresistant SCLC cells and are linked with poorer patient outcomes. Their studies showed that PRMT1 contributes to resistance by activating SOX2-mediated stemness properties in tumors. When PRMT1 was inhibited, there was a reduction in these properties and an increase in sensitivity to cisplatin, making the PRMT1-SOX2 pathway an attractive target for therapy.
The researchers created a DNA nanomachine capable of carrying both the PRMT1 inhibitor DCLX069 and cisplatin. The system is designed so that DCLX069 is released quickly inside tumor cells to reduce stemness before cisplatin is gradually delivered for maximum effect. Laboratory and animal tests demonstrated that this method reversed chemoresistance and slowed tumor growth more effectively than conventional intravenous cisplatin treatment.
Additionally, use of the DNA nanomachine reduced common side effects associated with cisplatin—such as blood-related and kidney toxicity—and did not trigger significant immune responses. This suggests it may be safer for patients compared to traditional methods.
Due to its programmable nature, this DNA-based technology could potentially be adapted for other types of chemoresistant cancers or tailored for personalized therapies. With further improvements in design, dosing strategies, and production methods, this platform could advance efforts to overcome chemoresistance in clinical settings.
"With further optimization of structural design, dosing regimens, and scalable manufacturing processes, this DNA nanomachine platform holds promise for advancing chemosensitization strategies toward clinical application and offers a novel solution for overcoming tumor chemoresistance," said Professor Zhang’s team.
