Site‐Specific MicroRNA‐33 Antagonism by pH‐Responsive Nanotherapies for Treatment of Atherosclerosis via Regulating Cholesterol Efflux and Adaptive Immunity

Abstract Atherosclerosis remains the leading cause of a broad spectrum of deadliest cardiovascular diseases. MicroRNA‐33 is a new therapeutic target for atherosclerosis due to its diverse functions. However, it remains a great challenge in clinical translation of nucleic acid‐based microRNA‐targeting therapeutics. Considering lesional acidosis, herein cyclodextrin‐derived pH‐responsive and integrin‐targeting nanoparticles containing an antisense oligonucleotide against microRNA‐33 (anti‐miR33) are engineered for precision therapy of atherosclerosis. A desirable anti‐miR33 nanotherapy (AAM NP) is initially developed by screening carrier materials. AAM NP is further decorated with a peptide ligand cRGDfK for integrin to afford an active targeting nanotherapy RAAM NP, to achieve more effective delivery of anti‐miR33 to plaques and target cells. Both nanotherapies can be efficiently internalized by different cells relevant to atherosclerosis. After intravenous delivery, AAM NP passively accumulates in atherosclerotic plaques and related cells in apolipoprotein E‐deficient mice. Correspondingly, AAM NP treatment significantly attenuates atherosclerosis in mice and notably reduces vulnerable plaques. Decoration with cRGDfK considerably enhances the targeting capability and therapeutic effects of RAAM NP. Mechanistically, anti‐miR33 nanotherapies significantly promote reverse cholesterol transport and notably regulate adaptive immunity via modulating macrophage polarization and regulatory T cell differentiation. Consequently, the pH‐responsive anti‐miR33 nanotherapies are promising for targeted treatment of atherosclerosis.