Drug delivery via inhalation is commonly used for respiratory disorders, but its potential for therapeutically targeting the heart has not been explored. Here, Miragoli et al. demonstrate in mice that following inhalation, their previously reported small, biocompatible and biodegradable negatively charged calcium phosphate nanoparticles (CaPs) cross the pulmonary barrier and reach the intracellular compartment within the heart. Inhalation of CaPs loaded with a cell-penetrating peptide that improves myocardial contraction restored cardiac function in a mouse model of diabetic cardiomyopathy. Intramyocardial delivery of a peptide-loaded CaP formulation was also demonstrated in pigs.