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

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 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 NPs might simultaneously reduce ROS levels ATR antioxidant activity and reduce inflammation the anti-inflammatory effect of RAP. In response to mildly acidic conditions mimicking the lesional inflammation , HR NPs dissociated and both ATR and RAP were effectively released. The developed HR NPs effectively inhibited pro-inflammatory macrophage proliferation, and displayed dose- and time-dependent specific internalization by different cellular models of atherosclerosis. Also, HR NP combination therapy showed an efficient synergetic anti-atherosclerotic effect 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 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 NPs attenuated RAP adverse effects and exhibited a good safety profile after long-term treatment in mice. Consequently, the developed pH-sensitive HR NP represent a promising nanoplatform for atherosclerosis combination therapy.