A biomimetic nanoplatform for endogenous self-replenishing of oxygen to promote sonodynamic therapy for targeted ablation of activated macrophages in atherosclerotic plaques

Atherosclerosis (AS) is a chronic inflammatory condition associated with increased morbidity and mortality. Nanomaterial-based sonodynamic therapy (SDT) shows considerable potential as a noninvasive treatment for AS. The impact of SDT is often limited by the unstable generation of reactive oxygen species (ROS) due to inadequate oxygen availability in the cellular microenvironment. In this study, a biomimetic nanoplatform (HMnO 2 -Ce6@MM; HMC@MM) was constructed by coating hollow manganese dioxide (HMnO 2 ) nanoparticles loaded with Chlorine e6 (Ce6) with macrophage membranes (MMs) to increase the ROS level for effective ablation of activated macrophages. HMC@MM is actively transported to activated macrophages in atherosclerotic plaques. In the slightly acidic and rich hydrogen peroxide (H 2 O 2 ) environment of plaques, HMnO 2 reacts with H 2 O 2 to produce Mn 2+ and oxygen. Mn 2+ is applicable in magnetic resonance imaging to detect unstable plaques. Under the condition of endogenous self-replenishing oxygen , HMC@MM-mediated SDT can produce sufficient ROS, subsequently initiating mitochondrial dysfunction and inducing the apoptosis of activated macrophages. Ablation of activated macrophages not only alleviated the inflammatory environment but the apoptotic fragments also triggered efferocytosis of fresh macrophages in the plaque, thereby effectively controlling unstable plaques. The HMC@MM-mediated SDT strategy has comprehensive effects on controlling atherosclerotic plaque progression. • Biomimetic Design :Constructed HMC@MM with HMnO 2 , Ce6, and MM; long-circulation, targeted to plaques, plaque imaging. • SDT Enhancement: HMC@MM produces O 2 in acidic plaque microenvironment, improves SDT. • Comprehensive Anti-AS Effects :Controls plaque progression, reduces inflammation, promotes efferocytosis.