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.
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