Professor Chao Zhang’s team at Southern Medical University Pearl River Hospital has developed a novel DNA nanomachine-based drug delivery and release strategy to overcome chemotherapy resistance in small cell lung cancer (SCLC). The research team identified the PRMT1/SOX2 signaling axis as a key driver of chemoresistance in SCLC, and based on this mechanism they designed DNA nanomachines that can be temporally programmed to release drugs. By precisely targeting chemoresistant tumor cells, the nanomachines rapidly release stemness inhibitors followed by sustained release of the chemotherapeutic agent cisplatin, effectively reversing tumor stemness and significantly increasing chemotherapy sensitivity.
Research background
Chemotherapeutic resistance remains one of the main causes of treatment failure in cancer treatment and is often associated with tumor invasion, increased metastasis, and poor prognosis. Beyond limited drug delivery efficiency, chemoresistance is strongly influenced by intrinsic cell signaling networks that modulate multiple biological properties. Among these, tumor stemness, defined by the capacity for self-renewal and differentiation, is widely recognized as a central factor in chemoresistance and tumor recurrence. However, the molecular mechanisms that control word stemness and effective strategies to target them remain incompletely understood.
Research progress
Professor Zhang’s team systematically elucidated the important role of PRMT1 in SCLC. Their findings showed that PRMT1 was significantly upregulated in chemoresistant SCLC cells and closely correlated with poor patient prognosis. Mechanistic studies revealed that PRMT1 promotes chemoresistance by activating SOX2-mediated tumor stemness. Inhibiting PRMT1 significantly reduced stemness and increased sensitivity to cisplatin, establishing the PRMT1-SOX2 axis as an important resistance-driving pathway and a promising therapeutic target.
Based on these insights, the researchers constructed a DNA nanomachine-based delivery system that simultaneously loaded the PRMT1 inhibitor DCLX069 and cisplatin. This system enables programmed therapeutic sequences within tumor cells. In other words, DCLX069 is rapidly released to suppress tumor stemness, followed by gradual release of cisplatin to maximize cytotoxic effects. DNA nanomachines have demonstrated excellent tumor targeting ability both in vitro and in vivo.
In cell and animal models, this nanotherapeutic system effectively reversed the chemoresistance of SCLC and significantly inhibited tumor growth. Compared with conventional intravenous administration of cisplatin, DNA nanomachines significantly reduced the hematologic and renal toxicity associated with cisplatin and did not induce obvious immunogenic responses, highlighting its favorable biosafety profile and strong potential for clinical application.
Future prospects
Due to the high programmability of DNA-based materials, this nanotherapeutic strategy could be extended to other chemotherapy-resistant tumor types and adapted for multitargeted, personalized precision therapy. By further optimizing the structural design, dosing regimen, and scalable manufacturing process, this DNA nanomachine platform has the potential to advance chemosensitization strategies toward clinical applications, providing a new solution to overcome tumor chemoresistance.
sauce:
Science and Technology Review Publishing
Reference magazines:
Chen, J. others. (2025). DNA nanomachines can temporally program drug release to modulate stem cell-related signaling pathways and overcome chemoresistance. the study. DOI: 10.34133/research.0999. https://spj.science.org/doi/10.34133/research.0999
