Heart failure is a serious clinical and public health problem. Currently there is an unmet demand for effective therapies for heart failure. Herein we reported noninvasive inhalation delivery of nanotherapies to prevent heart failure./nMethods: A reactive oxygen species (ROS)-scavenging material (TPCD) was synthesized, which was processed into antioxidative and anti-inflammatory nanoparticles (i.e., TPCD NP). By decoration with a mitochondrial-targeting moiety, a multilevel targeting nanotherapy TTPCD NP was engineered. Pulmonary accumulation of inhaled TPCD NP and underlying mechanisms were examined in mice. In vivo efficacies of nanotherapies were evaluated in mice with doxorubicin (DOX)-induced cardiomyopathy. Further, an antioxidative, anti-inflammatory, and pro-resolving nanotherapy (i.e., ATTPCD NP) was developed, by packaging a peptide Ac2-26. In vitro and in vivo efficacies of ATTPCD NP were also evaluated./nResults: TPCD NP alleviated DOX-induced oxidative stress and cell injury by internalization in cardiomyocytes and scavenging overproduced ROS. Inhaled TPCD NP can accumulate in the heart of mice by transport across the lung epithelial and endothelial barriers. Correspondingly, inhaled TPCD NP effectively inhibited DOX-induced heart failure in mice. TTPCD NP showed considerably enhanced heart targeting capability, cellular uptake efficiency, and mitochondrial localization capacity, thereby potentiating therapeutic effects. Notably, TPCD NP can serve as bioactive and ROS-responsive nanovehicles to achieve combination therapy with Ac2-26, affording further enhanced efficacies. Importantly, inhaled TPCD NP displayed good safety at a dose 5-fold higher than the efficacious dose./nConclusions: Inhalation delivery of nanoparticles is an effective, safe, and noninvasive strategy for targeted treatment of heart diseases. TPCD NP-based nanotherapies are promising drugs for heart failure and other acute/chronic heart diseases associated with oxidative stress.

中文翻译：

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肺循环介导的心脏靶向通过吸入内在生物活性纳米粒子预防心力衰竭

心力衰竭是一个严重的临床和公共卫生问题。目前，对心力衰竭的有效疗法的需求尚未得到满足。在此，我们报道了纳米疗法的无创吸入递送以预防心力衰竭。/n方法：合成了一种活性氧（ROS）清除材料（TPCD），将其加工成抗氧化和抗炎纳米颗粒（即TPCD NP）。通过修饰线粒体靶向部分，设计了多级靶向纳米疗法TTPCD NP。在小鼠中检查了吸入 TPCD NP 的肺积聚和潜在机制。体内在患有阿霉素（DOX）诱导的心肌病的小鼠中评估了纳米疗法的功效。此外，通过包装肽Ac2-26，开发了一种抗氧化、抗炎和促解决的纳米疗法（即ATTPCD NP）。还评估了 ATTPCD NP 的体外和体内功效。/n结果：TPCD NP 通过心肌细胞内化和清除过量产生的 ROS 来缓解 DOX 诱导的氧化应激和细胞损伤。吸入的 TPCD NP 可通过转运穿过肺上皮和内皮屏障而在小鼠心脏中积累。相应地，吸入 TPCD NP 可有效抑制 DOX 诱导的小鼠心力衰竭。TTPCD NP 显示出显着增强的心脏靶向能力、细胞摄取效率和线粒体定位能力，从而增强了治疗效果。值得注意的是，TPCD NP 可以作为具有生物活性和 ROS 响应性的纳米载体来实现与 Ac2-26 的联合治疗，从而进一步提高疗效。重要的是，吸入 TPCD NP 在比有效剂量高 5 倍的剂量下表现出良好的安全性。/n结论：纳米颗粒的吸入给药是一种有效、安全、无创的靶向治疗心脏病的策略。基于 TPCD NP 的纳米疗法是治疗心力衰竭和其他与氧化应激相关的急性/慢性心脏病的有前途的药物。