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Integrin α7 Defines a Profibrotic and Proinflammatory Adipose Stromal Population Targeted for Nanoparticle PAI-1 Gene Silencing in Obesity
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DOI：10.1016/j.ymthe.2026.08.005.png)
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Abstract
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Obesity-associated metabolic dysfunction is driven not only by adipocyte expansion but also by pathological remodeling of adipose tissue mediated by distinct stromal cell subpopulations. However, the lack of strategies to selectively interrogate and therapeutically modulate these pathogenic cells has limited clinical progress. Here, we identify integrin α7 (ITGA7)-expressing adipose stromal cells (ASCs) as a proinflammatory and profibrotic population that contributes to adipose tissue dysfunction in obesity and introduce a targeted nanotherapy to selectively reprogram their inflammatory signaling. ITGA7high ASCs from obese white adipose tissue display a profibrotic, proinflammatory phenotype with impaired adipogenic capacity, exacerbated by inflammatory stress. To selectively target this subset, we engineered lipid-coated mesoporous silica nanoparticles functionalized with anti-ITGA7 antibodies, which exhibit preferential uptake by ITGA7high ASCs in vitro and in vivo. Leveraging this platform, we delivered siRNA against plasminogen activator inhibitor-1 (PAI-1), a key regulator of obesity-associated inflammation and fibrosis. In obese mice, ITGA7-targeted siRNA nanotherapy selectively accumulates in white adipose tissue and effectively silences PAI-1 expression at both the tissue level and within ITGA7high ASCs. Together, these findings establish ITGA7 as a therapeutically accessible marker of pathogenic ASC and define a molecular therapy framework for cell-selective genetic intervention within stromal niches in obesity.
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