Oxygen-carrying microfluidic microcapsules for enhancing chemo-sonodynamic therapy on patient-derived tumor organoid models

• Hypoxia restricts the anti-tumor efficacy. • Perfluorocarbon has excellent oxygen solubility. • Multi-agent co-delivery microcapsules fabricated via microfluidics. • Oxygen can enhance the tumor-killing effect of chemo-sonodynamic therapy. Tumor hypoxia restricts anti-tumor efficacy of aerobic therapies such as chemotherapy and sonodynamic therapy (SDT), and efforts in this area are focused on developing biocompatible and stable oxygen carrying platforms for the anti-tumor treatments. Herein, we present a novel microcapsule delivery system with perfluorocarbon (PFC) core carrying oxygen, and hydrogel shell encapsulating antimetabolite gemcitabine (Gem) and sonosensitizer indocyanine green (ICG) (PO/GI-MCs) for enhancing the efficacy of chemo-sonodynamic therapy against pancreatic cancer. It is demonstrated that the PO/GI-MCs could reverse the hypoxic microenvironment, enhance the reactive oxygen species production during SDT, and induce cytotoxicity with assistance from the simultaneously release of Gem in presence of low intensity ultrasound. The PO/GI-MCs could realize a synergistic therapy and achieve a significantly enhanced anti-tumor effect in patient-derived pancreatic cancer organoid models. Therefore, we believe that the proposed oxygen-carrying microfluidic microcapsules can be an effective strategy for enhancing chemo-sonodynamic therapy for hypoxic tumors.