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

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 H₂O₂ 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.