Closed‐Loop Control of Macrophage Engineering Enabled by Focused‐Ultrasound Responsive Mechanoluminescence Nanoplatform for Precise Cancer Immunotherapy

Macrophage engineering has emerged as a promising approach for modulating the anti-tumor immune response in cancer therapy. However, the spatiotemporal control and real-time feedback of macrophage regulatory process is still challenging, leading to off-targeting effect and delayed efficacy monitoring therefore raising risk of immune overactivation and serious side effects. Herein, a focused ultrasound responsive immunomodulator-loaded optical nanoplatform (FUSION) is designed to achieve spatiotemporal control and status reporting of macrophage engineering in vivo. Under the stimulation of focused ultrasound (FUS), the immune agonist encapsulated in FUSION can be released to induce selective macrophage M1 phenotype differentiation at tumor site and the near-infrared mechanoluminescence of FUSION is generated simultaneously to indicate the initiation of immune activation. Meanwhile, the persistent luminescence of FUSION is enhanced due to hydroxyl radical generation in the pro-inflammatory M1 macrophages, which can report the effectiveness of macrophage regulation. Then, macrophages labeled with FUSION as a living immunotherapeutic agent (FUSION-M) are utilized for tumor targeting and focused ultrasound activated, immune cell-based cancer therapy. By combining the on-demand activation and feedback to form a closed loop, the nanoplatform in this work holds promise in advancing the controllability of macrophage engineering and cancer immunotherapy for precision medicine.