Targeted therapy of atherosclerosis by pH-sensitive hyaluronic acid nanoparticles co-delivering all-trans retinal and...

Atherosclerosis, the leading cause of death in the elderly worldwide, is typically characterized by elevated reactive oxygen species (ROS) levels and a chronic inflammatory state at the arterial plaques. Herein, pH-sensitive nanoparticles (HR_RAP NPs) co-delivering all-trans retinal (ATR), an antioxidant linked to hyaluronic acid (HA) through a pH-sensitive hydrazone bond, and rapamycin (RAP), an anti-atherosclerotic drug loaded into the nanoparticle core, are developed for targeted combination therapy of atherosclerosis. In this way, HR_RAP NPs might simultaneously reduce ROS levels via ATR antioxidant activity and reduce inflammation via the anti-inflammatory effect of RAP. In response to mildly acidic conditions mimicking the lesional inflammation in vitro, HR_RAP NPs dissociated and both ATR and RAP were effectively released. The developed HR_RAP NPs effectively inhibited pro-inflammatory macrophage proliferation, and displayed dose- and time-dependent specific internalization by different cellular models of atherosclerosis. Also, HR_RAP NP combination therapy showed an efficient synergetic anti-atherosclerotic effect in vitro by effectively inhibiting the inflammatory response and oxidative stress in inflammatory cells. More importantly, HR NPs specifically accumulated in the atherosclerotic plaques of apolipoprotein E-deficient (ApoE^-/-) mice, by active interaction with HA receptors overexpressed by different cells of the plaque. The treatment with HR_RAP NPs remarkably inhibited the progression of atherosclerosis in ApoE^-/- mice which resulted in stable plaques with considerably smaller necrotic cores, lower matrix metalloproteinase-9, and decreased proliferation of macrophages and smooth muscle cells (SMCs). Furthermore, HR_RAP NPs attenuated RAP adverse effects and exhibited a good safety profile after long-term treatment in mice. Consequently, the developed pH-sensitive HR_RAP NP represent a promising nanoplatform for atherosclerosis combination therapy.