Multifunctional DNA nano-sponge system for targeted sensitization of ovarian cancer chemotherapy via metabolic reprogramming and ferroptosis induction.

The inefficacy of chemotherapy in ovarian cancer, hindered by poor targeting and multiple drug resistance, is intricately linked to the tumor micro-environment and abnormal metabolic patterns. Here, we present ZnO@DS-DOX, an innovative nanomaterial that integrates small-sized ZnO nanoparticles with oxygen vacancies, embedded within 2D-ZnMOF and encapsulated in a DNA nanosponge, to enhance doxorubicin delivery. This system targets ovarian cancer cells specifically through the MUC1 aptamer and remodels metabolic signaling within the tumor microenvironment. ZnO alleviates hypoxia and reduces chemoresistance by catalyzing HO, while Zn release activates DNAzymes to target HIF-1a mRNA. The system reduces the efflux of chemotherapy drugs and inhibits cellular glycolysis. Disrupting the Warburg effect enhances mitochondrial respiration, increases ROS levels, disrupts the redox system, and induces ferroptosis, thereby significantly improving therapeutic efficacy. The uptake rate of ovarian cancer cells for the system was nearly 15 times higher than that of normal cells. Following treatment, the IC50 value of ovarian cancer cells decreased by approximately 72.7 %. Our in vitro and in vivo studies demonstrate that ZnO@DS-DOX effectively modulates tumor metabolic pathways, mitigates drug resistance, and enhances treatment outcomes, representing a significant advancement in nanomedicine and cancer therapy.