VISTA antibody-loaded Fe3O4@TiO2 nanoparticles for sonodynamic therapy-synergistic immune checkpoint therapy of pancreatic cancer
Lu Hong, Kaiwei Xu, Ming Yang, Lubing Zhu, Chunqu Chen, Xu Liu, Weihao Zhu, Lufei Jin, Linwei Wang, Jie Lin, Jianhua Wang, Wenzhi Ren, Aiguo Wu
Abstract
Breaking the poor permeability of immune checkpoint inhibitors (ICIs) caused by the stromal barrier and reversing the immunosuppressive microenvironment are significant challenges in pancreatic cancer immunotherapy. In this study, we synthesized core-shell Fe3O4@TiO2 nanoparticles to act as carriers for loading VISTA monoclonal antibodies to form Fe3O4@TiO2@VISTAmAb (FTV). The nanoparticles are designed to target the overexpressed ICIs VISTA in pancreatic cancer, aiming to improve magnetic resonance imaging-guided sonodynamic therapy (SDT)-facilitated immunotherapy. Laser confocal microscopy and flow cytometry results demonstrate that FTV nanoparticles are specifically recognized and phagocytosed by Panc-2 cells. In vivo experiments reveal that ultrasound-triggered TiO2 SDT can induce tumor immunogenic cell death (ICD) and recruit T-cell infiltration within the tumor microenvironment by releasing damage-associated molecular patterns (DAMPs). Furthermore, ultrasound loosens the dense fibrous stroma surrounding the pancreatic tumor and increases vascular density, facilitating immune therapeutic efficiency. In summary, our study demonstrates that FTV nanoparticles hold great promise for synergistic SDT and immunotherapy in pancreatic cancer.