Core–Satellite Nanoassembly Overcomes Spatial Heterogeneity of Dendric Cell Distribution in Pancreatic Tumors for Effective Chemoimmunotherapy

Pancreatic cancer therapies such as chemotherapy and immunotherapy are hindered by the dense extracellular matrix known as physical barriers, leading to heterogeneity impeding the effective penetration of chemotherapeutic agents and activation of antitumor immune responses. To address this challenge, we developed a hybrid nanoassembly with a distinct core-satellite-like heterostructure, PLAF@P/T-PD, which is responsive to both internal pH/redox and external ultrasound stimulations. This heterostructural nanoassembly features a polymersome core encapsulating an ultrasound contrast agent perfluoropentane and a chemotherapeutic agent Taxol (PLAF@P/T) electrostatically coated with satellite-like polyplexes carrying an immune agonist dsDNA (PD), which brings about synergistic functions inside the pancreatic tumor. The PLAF@P/T core functions as an enhancer for intratumor delivery through size enlargement and charge conversion in response to reactive oxygen species (ROS) and low pH, which triggers polyplex release and enables ultrasound-assisted tumor-penetrating Taxol delivery. Meanwhile, the released cationic polyplexes function as nucleic nanomedicine preferentially engulfed by peripheral dendritic cells (DCs) for immune modulation. Animal studies in mouse orthotopic pancreatic tumor model demonstrated exceptional therapeutic efficacy against both primary and metastatic tumors, which underlines the potential of this heterostructural nanoplatform for overcoming the therapeutic challenges associated with the heterogeneous physical barrier hindering intratumor drug delivery in pancreatic cancer treatment.