Magnetic Navigation of Spatiotemporally Synergistic Delivery to Potentiate Sonodynamic Therapy of Orthotopic Pancreatic Carcinoma

Abstract Pancreatic cancer remains one of the most challenging malignancies to treat due to its aggressive nature and the dense fibrotic stroma that severely hinders effective drug penetration. In this study, a spatiotemporally synergistic delivery strategy based on magnetic navigation is developed to enhance the efficacy of sonodynamic therapy in orthotopic pancreatic cancer. This approach involved employing hollow mesoporous iron oxide to carry the sonosensitizer, [Ru(bpy) 3 ] 2+ , and conjugating iRGD on the surface, leveraging excellent magnetic responsiveness for directional driving under magnetic fields. The feasibility and delivery efficiency of magnetic navigation are further confirmed in fibrotic pancreatic tumors through an optimized tumor suspension model, innovatively tailored for the implementation of magnetic manipulation. A combination of histological, imaging, and quantitative analyses confirmed that precise anatomical positioning enabled magnetic field–guided delivery to achieve significant nanoparticle accumulation at the pancreatic tumor site. When combined with iRGD, this complementary approach further enhanced intratumoral enrichment by ≈2.9 fold and significantly amplified the therapeutic efficacy of sonodynamic therapy. Moreover, the system demonstrated excellent biocompatibility and safety throughout the treatment process. Collectively, these findings underscore the synergistic potential of magnetic navigation and iRGD for precise and effective sonodynamic therapy of pancreatic cancer.