Ultrasound‐Propelled Nanomotors Enable Activatable Near‐Infrared‐II Fluorescence Imaging‐Guided Synergistic Oxygen‐Independent and Oxygen‐Dependent Sonodynamic Therapy of Atherosclerosis

Abstract Sonodynamic therapy (SDT) holds great promise as a therapeutic approach for treating atherosclerotic plaque. However, the therapeutic efficacy of SDT is hindered by the restricted tissue penetration depth and insufficient generation of reactive oxygen species (ROS) associated with conventional sonosensitizers. Furthermore, determining the optimal timing for ultrasound (US) irradiation after the administration of sonosensitizers presents a significant technical challenge. Addressing these issues is crucial for enhancing the effectiveness of SDT. Herein, a hyaluronic acid‐modified US‐propelled Janus mesoporous SiO₂ partially coated gold nanorods loaded with 2,2‐azobis[2‐(2‐imidazolin‐2‐yl) propane] dihydrochloride (AIPH) is developed, along with functionalized Ag/Ag₂S nanoparticles (HA‐JASAA), for near‐infrared‐II (NIR‐II) fluorescence imaging‐guided SDT of atherosclerotic plaque. Following intravenous administration of HA‐JASAA, the hyaluronic acid modification enables specific targeting of proinflammatory macrophages within atherosclerotic plaques. Subsequently, upon reacting with H₂O₂ in the atherosclerotic microenvironment, it turns on the NIR‐II fluorescence signal. US irradiation is applied when the intensity of NIR‐II fluorescence signal reaches its peak; AIPH loaded in HA‐JASAA undergoes conversion into nitrogen propelling the HA‐JASAA toward deep penetration into plaque tissue. Furthermore, under US activation, two sonosensitizers, AIPH and Ag₂S, generate oxygen‐independent and oxygen‐dependent ROS respectively to induce apoptosis of lesional macrophages, thereby significantly inhibiting the progression of atherosclerotic plaque.