Abstract Body: Introduction: Peripheral artery disease (PAD) lacks effective therapies that directly target the inflammatory and biomechanical drivers of femoral plaque progression. Macrophages play a central role in plaque growth, but selective targeting of plaque-resident macrophages remains challenging. We developed a mechanical stress-responsive, dual-receptor-targeted nanotherapy to deliver the PIEZO1 inhibitor GsMTx4 specifically to femoral plaque macrophages. Hypothesis: Nanoparticle-mediated PIEZO1 inhibition will attenuate macrophage-driven PAD progression through modulation of PIEZO1-Notch1 signaling. Methods: A murine PAD model was established using partial femoral artery ligation combined with AAV-PCSK9 injection and high-fat diet. Hyaluronic acid nanoparticles conjugated with the uPA amino-terminal fragment (ATF) were engineered to target plaque macrophage uPAR and CD44 receptors and deliver GsMTx4 (ATF/HANP/GsMTx4). PIEZO1-Notch1 signaling was examined in PAD arteries under disturbed flow and in macrophages exposed to oscillatory shear stress in vitro. Results: The PAD model reproducibly produced robust femoral plaques with elevated PIEZO1 expression. Systemic delivery of GsMTx4-loaded HANPs reduced plaque burden, femoral stiffness, lipid accumulation, and macrophage content in vivo. Moreover, PIEZO1 inhibition also diminished monocyte adhesion to human aorta ECs (HoAECs) under pro-atherogenic conditions in vitro. ATF conjugation enhanced macrophage-specific nanoparticle uptake in atherosclerotic plaques in APOE knockout mice and cultured macrophages. Mechanistically, PIEZO1 inhibition increased macrophage Notch1 expression in PAD arteries under disturbed flow. Whereas PIEZO1 activation increased Notch1 intracellular domain levels under laminar shear stress but decreased them under oscillatory shear stress. Conclusions: ATF/HANP/GsMTx4 is a first-in-class nanotherapy that selectively targets mechanosensitive signaling in plaque macrophages, revealing a critical role for flow-dependent PIEZO1-Notch1 signaling in femoral PAD progression.