Abstract We0076: Targeted Nanotherapy for PAD: Hyaluronic Acid-based Platforms and PIEZO1 Modulation to Improve Vascular Health

Background and Aims: Peripheral Arterial Disease (PAD) is a progressive vascular disorder affecting millions, leading to critical limb ischemia, amputation, and increased cardiovascular mortality. Current treatments inadequately address PAD-specific outcomes, underscoring the urgent need for innovative therapies. Our study aims to develop a novel therapeutic platform combining hyaluronic acid-based nanoparticles (HANPs) to deliver the PIEZO1 inhibitor, GsMTx4, specifically to atherosclerotic plaques. We hypothesize that this targeted nanotherapy can melt femoral plaque in our established murine PAD model. Methods: Male and female S129 mice were infected with AAV-PCSK9 and started on a high-fat diet. 1 Week later, mice underwent unilateral partial femoral artery ligation (PFL). The PIEZO1 (a mechano-sensor) inhibitor GsMTx4 was encapsulated by HANPs (HANP-GsMTx4). 2 weeks after PFL surgery, mice were i.v. injected with HANP-GsMTx4. 4 weeks after PFL surgery, Mice were sacrificed to examine the therapeutic efficacy of HANP-GsMTx4. Results: Robust atherosclerotic plaque developed in our murine PAD model with increased expression of PIEZO1. Systemic treatment of HANP-GsMTx4 significantly reduces plaque size and CD68 + cell number in male femoral plaques, without affecting lipid deposition. Pharmacological inhibition of PIEZO1 suppresses endothelial cell recruitment of monocytes and favors macrophage efferocytosis in vitro . Conclusions: Our novel HANP-GsMTx4 nanoparticle has a strong anti-atherosclerotic effect on femoral artery plaque. This is the first application of nanomedicine to murine PAD model, providing a foundation for future translational studies.