uPAR-Guided Dendrimer Gel Nanoparticles Reprogram Inflammation to Stabilize Atherosclerotic Plaques.

Authors

Hsin-Yin Chuang, Huari Kou, Yue-Wern Huang, Hu Yang

Published in

ACS applied materials & interfaces. Jun 24, 2026. Epub Jun 24, 2026.

Abstract

Atherosclerosis is characterized by lipid deposition, chronic inflammation, and apoptosis within the arterial wall, leading to plaque progression and instability. Current lipid-lowering therapies fail to fully address residual cardiovascular risk driven by local inflammation and cell death. Here, we report the development of uPA-functionalized, rapamycin-encapsulated dendrimer nanoparticles (G5PM-uPA/RA) that preferentially accumulate in urokinase plasminogen activator receptor (uPAR)-enriched atherosclerotic plaque, including macrophage- and apoptosis-rich lesion microenvironments. G5PM-uPA/RA was constructed by cross-linking reaction-enabled flash nanoprecipitation in a custom-made multi-inlet vortex mixer, followed by thiol-maleimide conjugation of uPA for uPAR-guided targeting. The nanoparticles demonstrated uniform morphology, favorable stability, and efficient rapamycin loading. In vitro, G5PM-uPA/RA exhibited enhanced macrophage uptake (1.3-fold than nontargeted form), sustained intracellular drug retention (2.2-fold than free drug), and effective suppression of inflammatory cytokine TNF-α release (-10%). In vivo biodistribution studies in Ldlr^-/- mice confirmed accumulation of G5PM-uPA/RA in aortic lesions. Four weeks of G5PM-uPA/RA treatment in Ldlr^-/- mice led to significant reduction in plaque burden (-52% in whole aorta, -41% in aortic root), necrotic core size (-68%), proinflammatory cytokines (-59% for TNF-α, -57% for IL-6), and apoptosis (-61%), while promoting fibrous cap thickening (+60%). Importantly, systemic toxicity was not observed. Collectively, these findings demonstrate that G5PM-uPA/RA offers an effective and safe strategy for inflammation modulation and plaque stabilization, providing a promising nanomedicine platform for atherosclerosis therapy.

PMID:
42340987
Bibliographic data and abstract were imported from PubMed on 25 Jun 2026.

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