Nebulized lung spheroid cell-derived exosomes ameliorate cardiopulmonary remodeling in PH-HFpEF via exosomal miR-150-5p regulation of PI3K-Akt-mTOR signaling.
A murine model of PH-HFpEF was successfully induced by high-fat diet feeding and validated by echocardiography and histologic assessment.
Daily nebulized LSC-Exo treatment for 3 weeks significantly improved right and left ventricular structural parameters in mice with established PH-HFpEF.
Transcriptomic profiling revealed that LSC-Exo therapy activated PI3K-Akt signaling in the lung and suppressed downstream mTOR signaling in the heart.
miR-150-5p-loaded exosomes recapitulated the majority of functional and structural improvements seen with LSC-Exo therapy and modulated mTOR pathway activity.
Inhibition of miR-150-5p within exosomes attenuated the therapeutic efficacy of LSC-Exo treatment in PH-HFpEF.
No safety concerns were observed with nebulized LSC-Exo therapy in the murine PH-HFpEF model.
This research suggests that a new inhaled therapy using tiny particles called exosomes, derived from lung cells grown in a lab (lung spheroid cells), can reverse the harmful changes to the heart and lungs caused by a serious condition called PH-HFpEF. PH-HFpEF is a combination of pulmonary hypertension (high blood pressure in the lungs) and heart failure where the heart's pumping function appears normal, and currently there are no treatments that actually address the underlying disease. In mice fed a high-fat diet to mimic this disease, daily inhalation of these exosomes for three weeks meaningfully improved heart structure on both sides of the heart, reduced abnormal blood flow through heart valves, and decreased thickening of the blood vessel walls in the lungs—without any observed safety problems. The study also investigated how this therapy works at a molecular level. Using large-scale gene expression analysis, the researchers found that the exosome treatment activated a beneficial signaling pathway (PI3K-Akt) in the lungs while calming down a different pathway (mTOR) in the heart. A small molecule carried inside the exosomes, called miR-150-5p, appeared to be the key driver of these effects: exosomes deliberately loaded with extra miR-150-5p produced most of the same benefits as the full therapy, while exosomes engineered to block miR-150-5p largely eliminated the therapeutic benefit. This research suggests that inhaled exosome-based therapies could represent a new approach to treating cardiopulmonary diseases like PH-HFpEF, and that a specific molecular cargo (miR-150-5p) within those exosomes plays a central mechanistic role. The non-invasive inhalation delivery route and the absence of observed safety issues support further development of this approach, though studies in larger animals and eventually humans would be needed before clinical use.
Cantor H, Zhu D, Li Z, Hu S, Popowski K, Liu M, et al.. (2026). Therapeutic Reversal of PH-HFpEF via Lung Spheroid Cell Exosomes.. ACS nano. https://doi.org/10.1021/acsnano.6c06951