A Non‐Metallic Nanozyme Ameliorates Pulmonary Hypertension Through Inhibiting ROS/TGF‐β1 Signaling

Abstract Pulmonary hypertension (PH) is a life‐threatening cardiovascular disease with a lack of effective treatment options. Nanozymes, though promising for PH therapy, pose safety risks due to their metallic nature. Here, a non‐metallic nanozyme is reported for the treatment of monocrotaline (MCT)‐induced PH with a therapeutic mechanism involving the ROS/TGF‐β1 signaling. The synthesized melanin‐polyvinylpyrrolidone‐polyethylene glycol (MPP) nanoparticles showcase ultra‐small size, excellent water solubility, high biocompatibility, and remarkable antioxidant capacity. The MPP nanoparticles are capable of effectively eliminating ROS in isolated pulmonary artery smooth muscle cells (PASMCs) from PH rats, and significantly reduce PASMC proliferation and migration. In vivo results from a PH model demonstrate that MPP nanoparticles significantly increase pulmonary artery acceleration time, decrease wall thickening and PCNA expression in lung tissues, as evidenced by echocardiograpy, histology and immunoblot analysis. Additionally, MPP nanoparticles treatment improve running capacity, decrease Fulton index, and attenuate right ventricular fibrosis in MCT‐PH rats by using treadmill test, picrosirius red, and trichrome Masson staining. Further transcriptomic and biochemical analyses reveal that inhibiting ROS‐driven activation of TGF‐β1 in the PA is the mechanism by which MPP nanoparticles exert their therapeutic effect. This study provides a novel approach for treating PH with non‐metallic nanozymes based on a well‐understood mechanism.