Biomimetic Nanoplatform-Mediated Protective Autophagy Blockage Enhancing Sonodynamic and Ca2+-Overload Combined Therapy for Colon Cancer

The application of a multimodal combination therapy based on a targeted nanodelivery system has been demonstrated to be more valuable in the treatment of cancer. In this work, a hollow polydopamine delivery system (CCC@HP@M) was designed to achieve sonodynamic and calcium-overload combined therapy for colon cancer. The CCC@HP@M exhibits both homologous tumour-targeting ability and pH-responsive drug release properties, enabling the simultaneous targeted delivery of CaO2 nanoparticles/sonosensitizer Ce6/autophagy inhibitor CQ. The CaO2 nanoparticles as calcium agents capable of triggering Ca2+ overload in tumor cells. The oxidative stress produced by sonodynamic therapy is facilitated by the disruption of calcium homeostasis to enhance the effect of Ca2+ overload-induced apoptosis. Furthermore, the O2 produced by CaO2 augments the sensitization of sonodynamic therapy. The autophagy inhibitor CQ can inhibit protective cellular autophagy, which is activated by sonodynamic therapy and Ca2+ overload. Consequently, autophagy blockage can ensure the therapeutic effect of sonodynamic and Ca2+-overload combined therapy for colon cancer. The results of experiments in vitro and in vivo demonstrate that the stimulus-responsive targeted delivery system achieves autophagy blockage augmented sonodynamic and Ca2+-overload combined therapy of colon cancer. This work offers a promising theoretical basis for optimizing combined treatment strategies for tumors and clinical translational applications.