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 37,982 cells from diabetic and nondiabetic 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 small interfering RNA-mediated silencing of PTTG1 restored pericyte stability and barrier-supporting function under high-glucose stress. In vivo, Pttg1 silencing via viral or pericyte-specific adeno-associated virus delivery improved retinal vascular integrity and reduced retinal vascular dysfunction in diabetic mice. Integrated transcriptomic and metabolomic profiling revealed that PTTG1 silencing reprogrammed metabolism, modulating glycolytic flux and attenuating oxidative stress. Furthermore, a therapeutic strategy using spherical nucleic acid-based siPttg1 nanocarriers (sTDN-siPttg1) substantially 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.