Biomimetic Nanoparticle with Glutathione Depletion and Amplified ROS Generation Capabilities for Synergistic Chemo-Sonodynamic Therapy in Squamous Cell Carcinomas

Nanomedicines for combining chemotherapy and sonodynamictherapy(SDT) have enormous potential in squamous cell carcinoma treatment.However, the therapeutic efficacy of noninvasive SDT is severely limitedbecause the generation of reactive oxygen species (ROS) by sonosensitizersis highly dependent on the levels of intracellular excess glutathione(GSH) in the tumor cells. To overcome this barrier, a red blood cell(RBC) membrane-camouflaged nanomedicine consisting of GSH-sensitivepolyphosphoester (SS-PPE) and ROS-sensitive polyphosphoester (S-PPE)was designed for the simultaneous delivery of the sonosensitizer hematoporphyrin(HMME) and chemotherapeutic agent docetaxel (DTXL) for effectivelyenhanced antitumor efficacy. In vitro and in vivo studies demonstrated that HMME-driven ROS generationunder ultrasound (US) inhibited SCC7 cell proliferation and acceleratedDTXL release to further kill tumor cells via thehydrophobic-hydrophilic transition of the nanoparticle core.Meanwhile, the disulfide bond of SS-PPE effectively consumes GSH toprevent ROS consumption. This biomimetic nanomedicine provides GSHdepletion and amplified ROS generation capabilities to achieve a novelsynergistic chemo-SDT strategy for squamous cell carcinomas.