Corneal biomechanical cues mediated by PAI-2: the origin of PM2.5-induced corneal disease.

The biomechanical signature is directly correlated with the progression of disease in multiple soft tissues. However, their variations and roles, particularly during the initiation period of the disease, remain unclear. Here, we report that PM2.5 exposure induces corneal biomechanical cues alterations prior to corneal injury, as evidenced by increased corneal hysteresis in humans, thickened corneal thickness in rats, and enhanced tensile stress and cortical stiffness in HCECs. Specifically, intracellular PAI-2 is identified as a crucial mediator of the biomechanical responses in HCECs. It modulates PM2.5-induced autophagy and inflammation through a PAI-2/myosin II/F-actin/YAP-positive feedback loop, which ultimately drives HCEC injury. Furthermore, extracellular secretory PAI-2 levels in tears reflect PM2.5-related corneal damage in real time, making it a specific biomarker for the early diagnosis when combined with biomechanical cues. Early intervention for PM2.5-induced ocular damage could be achieved by developing an LNP-siPAI-2 ocular local delivery system targeting intracellular PAI-2. Overall, we propose that biomechanical cues in conjunction with specific biomarkers may serve as targets for the early diagnosis and intervention of soft tissue diseases.