Ultrasound-Driven Biomimetic Nanosystem Suppresses Tumor Growth and Metastasis through Sonodynamic Therapy, CO Therapy, and Indoleamine 2,3-Dioxygenase Inhibition

The rational design of nanoplatforms to bypass reticuloendothelial system (RES) clearance, enhance spatiotemporal controllability, and boost host immune responses to achieve synergized tumor-targeted therapeutic purpose is highly desired. Herein, a biomimetic nanosystem is developed for tumor-targeted in situ delivery of singlet oxygen (¹O₂) and carbon monoxide (CO) in response to exogenous stimulus ultrasound (US) and endogenous stimulus hydrogen peroxide (H₂O₂) in tumor microenvironment, respectively. Taking advantages of tumor homing and RES evasion abilities of the macrophage membrane coating, our designed nanosystem shows excellent accumulation at the tumor site and effective suppression of tumor growth through US/H₂O₂-generated ¹O₂ and CO to induce cell apoptosis and mitochondrial dysfunction. Furthermore, our nanosystem can induce significant tumor immunogenic death by ¹O₂/CO therapy, then can achieve effective immune responses and long-term immune memory through the combination of indoleamin 2,3-dioxygenase (IDO) signal blocking to effectively against tumor rechallenge and prevent lung metastasis. Taken together, the here-presented therapeutic strategy based on sonodynamic/CO therapy and IDO signaling inhibition might provide a promising perspective for synergistically treating cancer in future clinical translations.