Intravenous delivery of FAP-targeted SIS3-loaded nanoparticles inhibited Smad3 phosphorylation, decreased cardiac fibrosis, and restored cardiac function in murine AMI and TAC models.
Does targeted delivery of SIS3 via FAP-functionalized nanoparticles reduce cardiac fibrosis and improve cardiac function in murine models of AMI and TAC?
FAP-targeted nanoparticle delivery of a Smad3 inhibitor effectively attenuates cardiac fibrosis and preserves cardiac function in murine models of acute ischemic and chronic pressure-overload injury.
Pathological cardiac fibrosis arising from acute/chronic myocardial injury drives ventricular remodeling, functional impairment, and elevated mortality through mechanisms lacking effective therapies. Central to fibrogenesis, myofibroblast activation via TGFβ1-Smad3 signaling necessitates targeted therapeutic strategies. Anti-fibroblast activation protein (FAP)-functionalized nanoparticles (NPs-SIS3-Ab) were fabricated using PLGA@PDA cores to deliver a Smad3 inhibitor (SIS3). In vitro targeting was assessed through confocal microscopy in TGFβ1-stimulated myofibroblasts. Therapeutic efficacy was evaluated in murine acute myocardial infarction (AMI) and transverse aortic constriction (TAC) models using in vivo imaging system, confocal microscopy, histopathology, transthoracic echocardiography and Western blotting. The NPs-SIS3-Ab nanoparticles demonstrated efficient SIS3 loading, antibody conjugation density, and colloidal stability. Anti-FAP antibody modification enabled specific targeting ability to myofibroblasts both in vitro and in vivo. NPs-SIS3-Ab significantly suppressed TGFβ1-Smad3 pathway activation of myofibroblast in vitro and furthermore, systemic intravenous delivery of NPs-SIS3-Ab markedly inhibited Smad3 phosphorylation, decreased cardiac fibrosis area and more importantly, restored cardiac function both in AMI and TAC models without evident side effects. This FAP-targeted nanoplatform achieves precision Smad3 inhibition, demonstrating dual efficacy against acute ischemic and chronic pressure-overload fibrosis while preserving systemic safety. Our findings establish a clinically translatable strategy for modulating pathological fibroblast activity in heart failure.
Chen et al. (Sat,) conducted a other in Cardiac fibrosis. NPs-SIS3-Ab (Anti-FAP antibody-conjugated SIS3-loaded PLGA@PDA nanoparticles) vs. PBS, empty NPs, NPs-SIS3, and free SIS3 was evaluated on Cardiac fibrosis area and cardiac function. Intravenous delivery of FAP-targeted SIS3-loaded nanoparticles inhibited Smad3 phosphorylation, decreased cardiac fibrosis, and restored cardiac function in murine AMI and TAC models.