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.