Functional targeting of PTTG1 in pericytes restores vascular integrity in diabetic retina

Pericyte loss is an early and critical event in the pathogenesis of diabetic retinopathy (DR), yet the molecular mechanisms underlying pericyte dysfunction remain incompletely understood. Using single-cell RNA sequencing, we generated a retinal cellular overview comprising 18,926 cells from diabetic and non-diabetic mice. We identified a previously unrecognized pericyte subpopulation defined by high expression of pituitary tumor transforming gene 1 (PTTG1), which was enriched in diabetic retina. Functional studies demonstrated that CRISPR/Cas9 or siRNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high-glucose stress. In vivo, knockdown of PTTG1 via lentiviral or pericyte-specific AAV delivery improved retinal vascular integrity and reduced retinal vascular function in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed PTTG1 knockdown reprogrammed metabolism by modulating glycolytic flux and attenuating oxidative stress. Furthermore, a therapeutic strategy employing spherical nucleic acid-based siPTTG1 nanocarriers (sTDN-siPTTG1) significantly ameliorated retinal vascular dysfunction in DR model. These findings suggest that PTTG1 is a critical regulator of pericyte metabolic homeostasis and microvascular function in DR, highlighting its translational potential as a therapeutic target for diabetic microvascular complications.