The therapeutic efficiency of sonodynamic therapy (SDT) mainly depends on the presence of oxygen (O₂) to generate harmful reactive oxygen species (ROS); thus, the hypoxic tumor microenvironment significantly limits the efficacy of SDT. Therefore, the development of oxygen-independent free radical generators and associated combination therapy tactics can be a promising field to facilitate the anticancer capability of SDT. In this study, a biomimetic drug delivery system (C-TiO₂/AIPH@PM) composed of an alkyl-radical generator (2,2′-azobis[2-(2-imidazolin-2-yl)propane] dihydrochloride, AIPH)-loaded C-TiO₂ hollow nanoshells (HNSs) as the inner cores, and a platelet membrane (PM) as the outer shells is successfully prepared for synergistic SDT and oxygen-independent alkyl-radical therapy. The PM encapsulation can significantly prolong the blood circulation time of C-TiO₂/AIPH@PM compared with C-TiO₂/AIPH while enabling C-TiO₂/AIPH@PM to achieve tumor targeting. C-TiO₂/AIPH@PM can efficiently produce ROS and alkyl radicals, which can achieve a more thorough tumor eradication regardless of the normoxic or hypoxic conditions. Furthermore, the generation of these radicals improves the efficiency of SDT. In addition, nitrogen (N₂) produced due to the decomposition of AIPH enhances the acoustic cavitation effect and lowers the cavitation threshold, thereby enhancing the penetration of C-TiO₂/AIPH@PM at the tumor sites. Both in vitro and in vivo experiments demonstrate that C-TiO₂/AIPH@PM possesses good biosafety, ultrasound imaging performance, and excellent anticancer efficacy. This study provides a new strategy to achieve oxygen-independent free radical production and enhance therapeutic efficacy by combining SDT and free radical therapy.

Single-atom nanozymes (SAZs) with peroxidase (POD)-like activity have good nanocatalytic tumor therapy (NCT) capabilities. However, insufficient hydrogen peroxide (H₂O₂) and hydrogen ions in the cells limit their therapeutic effects. Herein, to overcome these limitations, a biomimetic single-atom nanozyme system was developed for self-enhanced NCT. We used a previously described approach to produce platelet membrane vesicles. Using a high-temperature carbonization approach, copper SAZs with excellent POD-like activity were successfully synthesized. Finally, through physical extrusion, a proton pump inhibitor (PPI; pantoprazole sodium) and the SAZs were combined with platelet membrane vesicles to create PPS. Both in vivo and in vitro, PPS displayed good tumor-targeting and accumulation abilities. PPIs were able to simultaneously regulate the hydrogen ion, glutathione (GSH), and H₂O₂ content in tumor cells, significantly improve the catalytic ability of SAZs, and achieve self-enhanced NCT. Our in vivo studies showed that PPS had a tumor suppression rate of > 90%. PPS also limited the synthesis of GSH in cells at the source; thus, glutamine metabolism therapy and NCT were integrated into an innovative method, which provides a novel strategy for multimodal tumor therapy.