Targeted Nanoparticle Delivery to Integrin alpha 7 Adipose Stromal Cells to Modulate Pro-Fibrotic and Pro-Inflammatory Adipose Tissue Microenvironment in Obesity

Obesity is a major public health challenge characterized by the expansion of white adipose tissue (WAT) and an increased risk of metabolic disorders, including diabetes, cardiovascular disease, and cancer. Within obese WAT, adipose stromal cells (ASCs) exhibit heterogeneity, with distinct subpopulations responding uniquely to altered extracellular matrix (ECM) cues. Our research investigates integrin alpha 7 (ITGA7) as a central mediator of this process and as a targeting strategy. We hypothesize ASCs expressing high levels of ITGA7 (ITGA7 high ) represent a pro-inflammatory, pro-fibrotic subpopulation contributing to obesity-associated dysfunction in white adipose tissue (WAT). By leveraging ITGA7 as a marker, we can engineer nanoparticles to selectively target and modulate the activity of this ASC subset, offering a novel therapeutic approach to reduce inflammation and fibrosis in obesity. To test this hypothesis, we isolated and sorted ITGA7 high and ITGA7 low ASCs from the WAT of obese and lean mice, assessing their adipogenic, inflammatory, and fibrotic profiles. ITGA7 high ASCs were also CD9 high , a marker associated with progenitor pools linked to fibrosis and metabolic dysfunction in obesity. Our results revealed that ITGA7 high ASCs exhibited elevated expression of ECM genes (Col1a1, Col3a1), decreased adipogenic markers (Pparg, Adiponectin), and increased inflammatory markers (PAI-1, Ccl2, Il6). In contrast, ITGA7 low ASCs displayed higher adipogenic potential, evidenced by greater lipid accumulation during differentiation, lipolysis, and glucose uptake. To selectively target ITGA7 high ASCs, we developed lipid-coated mesoporous silica nanoparticles (LCMSN) conjugated with anti-ITGA7 antibodies. In vitro studies demonstrated specific targeting and enhanced uptake of LCMSNs by ITGA7 high ASCs compared to ITGA7 low ASCs. To further assess the therapeutic potential, we loaded LCMSNs with PAI-1 siRNA. Silencing PAI-1, an inflammatory adipokine associated with fibrosis, led to a significant (50%) reduction in PAI-1 expression and a corresponding decrease in inflammatory markers. In vivo, we administered ITGA7-LCMSNs subcutaneously to ob/ob mice, observing strong retention in obese WAT 48 hours post-injection. Importantly, LCMSNs effectively silenced PAI-1 expression in obese WAT. These findings support the potential of targeting ITGA7 high ASCs using nanomedicine to mitigate obesity-induced inflammation and fibrosis, offering a promising therapeutic strategy to improve metabolic health in obesity. This work was partially funded by The University of Texas at San Antonio and the Voelcker Fund and TRC4 (Trauma Research and Combat Casualty Care Collaborative Award 175167) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.