A Hypoxia‐Responsive Single‐Atom Sonozyme for Targeted Sonocatalytic Therapy in Alleviating Atherosclerotic Plaque

Abstract Sonocatalytic therapy (SCT) offers a non‐invasive and deep tissue‐penetrating approach to addressing the pathological challenges of atherosclerosis. However, its therapeutic efficacy remains limited by the lack of efficient sonosensitizers. A critical challenge in SCT is simultaneously leveraging beneficial plaque microenvironment factors, such as elevated H ₂ O ₂ levels, while mitigating adverse conditions, including hypoxia. Herein, a microenvironment‐regulatable single‐atom sonozyme system is presented to enable effective SCT while simultaneously refining the lesion microenvironment. The single‐atom manganese catalyst (SMC) is synthesized via MOF‐derived precursor pyrolysis followed by ion implantation, yielding atomically precise four‐coordinated active sites. Functionalized with hyaluronic acid (HA) facilitates targeted delivery of SMC‐HA to M1 macrophages. Under ultrasound (US), SMC‐HA effectively eliminates M1 macrophages, thereby reducing plaque burden and promoting lesion regression in two ApoE ^−/− mice models. Overall, SMC‐HA reinforces its role as an advanced sonosensitizer for SCT. This study establishes SMC‐HA‐mediated SCT as a promising therapeutic strategy for atherosclerotic plaque treatment.