Therapeutic Reversalof PH-HFpEF via Lung SpheroidCell Exosomes

Pulmonary hypertension–associated heart failure with preserved ejection fraction (PH-HFpEF) is a prevalent and lethal cardiopulmonary syndrome without effective disease-modifying therapy. We investigated the therapeutic potential of lung spheroid cell–derived exosomes (LSC-Exos) in a murine model of PH-HFpEF induced by high-fat diet feeding. The disease phenotype was validated by echocardiography and histologic assessment. Mice with established PH-HFpEF received daily nebulized LSC-Exo for 3 weeks. Treatment significantly improved right and left ventricular structural parameters, reduced regurgitation velocity, and attenuated pulmonary vascular wall thickening compared with untreated controls. Transcriptomic profiling revealed activation of PI3K-Akt signaling in the lung and suppression of downstream mTOR signaling in the heart following LSC-Exo therapy, with marked upregulation of miR-150-5p in cardiac tissue. To define the mechanistic contribution, diseased mice were treated with miR-150-5p-enriched exosomes or exosomes containing a miR-150-5p inhibitor. miR-150-5p-loaded exosomes recapitulated the majority of functional and structural improvements and modulated mTOR pathway activity, whereas inhibition of miR-150-5p attenuated therapeutic efficacy. No safety concerns were observed. These findings demonstrate that nebulized LSC-Exo therapy ameliorates cardiopulmonary remodeling in PH-HFpEF and identify exosomal miR-150-5p as a key mediator of therapeutic benefit via regulation of PI3K-Akt-mTOR signaling. This study supports the development of inhaled exosome-based therapies for cardiopulmonary vascular disease.