A tetrahedral DNA nanoplatform with ultrasound-triggered biomimetic nanocarriers for targeted siMCM2 delivery and reversal of imatinib resistance in gastrointestinal stromal tumors

• MCM2 identified as a novel target to overcome imatinib resistance in GISTs. • Biomimetic TMB@TDN-iRGD-siMCM2 platform enhances tumor targeting and drug stability. • Ultrasound-mediated system significantly improves imatinib sensitivity in GISTs. • In vitro and in vivo models show robust tumor growth suppression with safety. • MCM2 played a key role in regulating tumor growth and drug responsiveness through Wnt/β-Catenin pathway. Imatinib resistance in gastrointestinal stromal tumors (GISTs) represents a significant therapeutic challenge. While current research focuses on KIT and PDGFRA genes, the mechanisms underlying resistance remain inadequately understood. This study aims to uncover novel genetic targets and mechanisms to overcome imatinib resistance, with a particular emphasis on MCM2, identified as a crucial factor in this resistance process. We engineered a biomimetic nanoscale microbubble (TMB@TDN-iRGD-siMCM2) utilizing GISTs-T1 cell membranes and lipid components. This system integrates siMCM2 and iRGD with tetrahedral DNA (TDN) to form a versatile platform, validated through polyacrylamide gel electrophoresis and atomic force microscopy. Characterization of the platform’s morphology, size, and zeta potential was conducted, and cellular uptake was assessed using confocal microscopy and flow cytometry. The efficacy of the ultrasound-mediated TMB@TDN-iRGD-siMCM2 platform combined with imatinib was evaluated in vitro and in a murine GISTs tumor model, with subsequent analysis of biodistribution and toxicity. The TMB@TDN-iRGD-siMCM2 platform effectively reversed imatinib resistance in GISTs when mediated by ultrasound. It demonstrated key properties including enhanced penetration, drug stability, and tumor targeting. The system significantly increased imatinib sensitivity and suppressed tumor growth while maintaining a favorable safety profile. This ultrasound-mediated biomimetic platform introduces a novel and efficient strategy for precise gene regulation in GISTs, markedly boosting imatinib’s anti-tumor efficacy. It holds considerable promise for advancing the treatment of GISTs and other solid tumors.