Macrophage-Targeted Sonodynamic/Photothermal Synergistic Therapy for Preventing Atherosclerotic Plaque Progression Using CuS/TiO₂ Heterostructured Nanosheets

Abstract

Sonodynamic therapy (SDT) and photothermal therapy (PTT) are two effective strategies for the treatment of atherosclerotic plaques. However, the low yield of reactive oxygen species (ROS) of conventional organic sonosensitizers and the low biosafety of hyperthermia limit the therapeutic efficacy of SDT and PTT. Herein, we report copper sulfide/titanium oxide heterostructure nanosheets modified with hyaluronic acid (HA) and PEG (HA-HNSs) for low-intensity sonodynamic and mild-photothermal synergistic therapy for early atherosclerotic plaques. CuS/TiO2 heterostructure nanosheets (HNSs) show high electron–hole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band. Moreover, HNSs exhibit intense absorbance in the NIR-II region, which endows the nanosheets with excellent photothermal performance. With a further modification of HA, HA-HNSs can selectively target intraplaque proinflammatory macrophages through CD44-HA interaction. Because SDT reduces the expression of heat shock protein 90 and PTT facilitates the sonocatalytic process, the combination of SDT and PTT based on HA-HNSs could synergistically induce proinflammatory macrophage apoptosis. More importantly, the synergistic therapy prevents the progression of early atherosclerotic plaque by removing lesional macrophages and mitigating inflammation. Taken together, this work provides a macrophage-targeting sonodynamic/photothermal synergistic therapy, which is an effective translational clinical intervention for early atherosclerotic plaques.

Research progress of stimuli-responsive ZnO-based nanomaterials in biomedical applications

“…85 Compared with conventional therapies, SDT, a hopeful non-invasive treatment technique, is implemented to target precisely the lesion location through the selection and modification of sonosensitizers, which leads to apoptosis of pathological cells, as well as less damage to normal cells and tissues. 86 It is noteworthy that the selection of sonosensitizers is one of the key links in achieving effective SDT. The ideal sonosensitizer should have good biosafety, precise aggregation targeting, high stability in specific environments and strong sensitivity to ultrasound.…”

Nanomaterial-based sonosensitizers: from exemplary design towards purposeful improvement

“…7A). 72 The CuS/ TiO 2 heterostructure nanosheets (HNSs) show high electronhole separation efficiency and superior sonodynamic performance, because it has high surface energy crystal facets as well as a narrow band (Fig. 7B).…”

“…The biomimetic delivery system with a natural cell membrane coating benefits from the diversity of surface antigens, thus eliminating the need for complex modification engineering. 72 Copyright 2022, American Chemical Society. (F) and (G) Reproduced with permission.…”

Ag-Doped Metal–Organic Frameworks’ Heterostructure for Sonodynamic Therapy of Deep-Seated Cancer and Bacterial Infection

“…Sonodynamic therapy (SDT) as an emerging external-stimuli-activated therapeutic modality utilizes sonosensitizers to generate cytotoxic reactive oxygen species (ROS) in an on-demand manner under the assistance of high-intensity-focused ultrasound (US). − Owing to the specificity of US to targeted lesion tissue, SDT exhibits minimized damage to the surrounding normal tissues compared to chemotherapeutic drugs or high-intensity-focused US, featured by noninvasiveness . Compared with the conventional ROS-mediated therapeutic strategies, such as photodynamic therapy (PDT) and radiodynamic therapy, SDT is intrinsically featured with a high tissue-penetrating ability and avoids the potential damage of radioactive rays, which has been extensively explored in the biomedical field, either in antitumor or antibacterial applications. − To date, considerable efforts have been denoted to develop various sonosensitizers with advanced sonosensitization capacity, ranging from organic and inorganic to hybrid materials . Inspired by photosensitizers for PDT, porphyrins and their derivatives as efficient sonosensitizers have been demonstrated to be activated under US irradiation to generate abundant ROS and kill cancer cells. − However, these traditional organic sonosensitizers suffer from low stability/solubility and fast excretion out from the body, which impede their extensive application and further clinical translation. , Semiconductor titanium dioxide (TiO 2 ) nanoparticles are the most representative paradigm of inorganic sonosensitizers .…”