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.

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Background Myocardial dysfunction is a critical cause of post‐cardiac arrest hemodynamic instability and circulatory failure that may lead to early mortality after resuscitation. Trimetazidine is a metabolic agent that has been demonstrated to provide protective effects in myocardial ischemia. However, whether trimetazidine protects against postresuscitation myocardial dysfunction is unknown. Methods and Results Cardiopulmonary resuscitation was initiated after 8 minutes of untreated ventricular fibrillation in Sprague‐Dawley rats. Animals were randomized to 4 groups immediately after resuscitation (n=15/group): (1) normothermia control (NTC); (2) targeted temperature management; (3) trimetazidine‐normothermia; (4) trimetazidine‐targeted temperature management. TMZ was administered at a single dose of 10 mg/kg in rats with trimetazidine. The body temperature was maintained at 34.0°C for 2 hours and then rewarmed to 37.5°C in rats with targeted temperature management. Postresuscitation hemodynamics, 96‐hours survival, and pathological analysis were assessed. Heart tissues and blood samples of additional rats (n=6/group) undergoing the same experimental procedure were collected to measure myocardial injury, inflammation and oxidative stress‐related biomarkers with ELISA‐based quantification assays. Compared with normothermia control, tumor necrosis factor‐α, and cardiac troponin‐I were significantly reduced, whereas the left ventricular ejection fraction and 96‐hours survival rates were significantly improved in the 3 experimental groups. Furthermore, inflammation and oxidative stress‐related biomarkers together with collagen volume fraction were significantly decreased in rats undergoing postresuscitation interventions. Conclusions Trimetazidine significantly alleviates postresuscitation myocardial dysfunction and improves survival by decreasing oxidative stress and inflammation in a ventricular fibrillation rat model. A single dose of trimetazidine administrated immediately after resuscitation can effectively improve cardiac function, whether used alone or combined with targeted temperature management.

We demonstrate that the traditional emulsification theory can be enriched by a self-assembly approach, in which hydrophilic copolymers with one block exhibiting noncovalent forces with the oil phase self-assemble at the oil-water interface, thereby reducing interfacial tension and forming emulsions. This approach was established using affinity diblock copolymers that can interact with oil molecules through electrostatic interactions or hydrogen-bonding. Nanoemulsions with excellent stability were successfully obtained simply via vortexing. The self-assembled emulsions showed unexpected catastrophic phase inversion, further extending the phase structures to bicontinuous and reverse emulsions. Complex emulsions could also be fabricated by this strategy. In addition, the thus prepared nanoemulsions can be used to engineer different nanomaterials.