Restoring Vascular Integrity with PLGA-Encapsulated PTEN Nanoparticles: A Multi-Pathway Strategy to Prevent Restenosis and Atherosclerotic Progression

About This Grant

ABSTRACT Cardiovascular diseases (CVD) are major chronic diseases and the leading cause of death in the United States and worldwide. Coronary artery disease (CAD), the most prevalent form of CVD, affects approximately 1 in 20 adults over 20 years old. Current treatments help manage risk factors but do not address thrombosis or restenosis comprehensively. Drug-eluting stents (DES) have improved restenosis rates but rely primarily on timed drug release, which fails to fully accommodate the multi-phase nature of vascular injury and repair. FDA approved DES effectively limit vascular smooth muscle cell (SMC) proliferation but also block endothelial growth required for vascular repair and has no effect on inflammation or chronic vascular remodeling resulting in incomplete healing, late stent thrombosis, and suboptimal long-term outcomes. PTEN is a key regulator of SMC function. Vascular SMCs are major contributors to pathological vascular remodeling through functional phenotypic modulation that plays a critical role in vascular disease progression. Our published and preliminary studies indicate that genetic and pharmacological upregulation/maintenance of PTEN levels actively preserves SMC phenotype, blocks inflammation, and prevents vascular disease progression in PTEN phosphatase- dependent and PTEN nuclear transcriptional-dependent manners. In contrast, SMC-specific depletion of PTEN exacerbates atherosclerotic lesion formation, injury-mediated restenosis, and hypertension-associated vascular remodeling making PTEN an essential and causal vascular protective target, which represents a novel concept for the treatment of cardiovascular disease. Unlike traditional DES, PTEN has been shown to directly target SMCs and block the major adverse events thereby mitigating neointimal hyperplasia, which is a major contributor to restenosis. Polymer poly-lactic-co-glycolic acid (PLGA) can be used as a promising delivery system due to their FDA approval, biodegradability, controlled drug release properties, cost-effectiveness, and commercial availability. These characteristics make PLGA polymers ideal for synthesizing PTEN encapsulated nanoparticles. For the current proposal, we hypothesize that engineered PTEN-PLGA nanoparticles will restore the contractile phenotype of SMCs, reducing proliferation, migration, and inflammation associated with restenosis. This approach has the potential to address critical gaps in current CAD treatment by offering a more precise and sustained intervention. As CVD cases continue to rise, developing a targeted therapeutic strategy is essential. A PTEN-PLGA nanoparticle system could transform restenosis prevention and provide a long-term solution to one of the biggest challenges in cardiovascular medicine. We propose that SMC targeted nanoparticle PTEN mRNA delivery will prevent SMC phenotypic modulation through PTEN-dependent maintenance of the contractile, differentiated VSMC phenotype and thereby inhibit in-stent restenosis. Two Aims are proposed to test engineered SMC-targeted PTEN-encapsulated PLGA nanoparticles in in vitro human SMC culture models and in vivo genetic mouse whole body delivery and rat stent-based delivery.