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. Methods: 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. Results: 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. Conclusions: 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.

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