Andrographolide-loaded PLGA nanoparticles protect retinal ganglion cells against experimental acute glaucomatous injury and attenuate mitochondrial dysfunction and retinal PANoptosis-related changes

ADR-NPs showed sustained release and acceptable short-term stability. • ADR-NPs showed preliminary short-term ocular and systemic tolerability. • ADR-NPs enhanced cellular and RGC protection relative to dose-matched free ADR. • ADR-NPs attenuated mitochondrial dysfunction and PANoptosis-related changes. • ADR-NPs preserved retinal structure and electrophysiological function after RIR. Acute glaucomatous injury is characterized by abrupt intraocular pressure elevation, retinal ischemia/reperfusion-like stress, and rapid retinal ganglion cell (RGC) degeneration, in which oxidative stress, mitochondrial dysfunction, and regulated cell death play important roles. Emerging evidence further implicates PANoptosis in glaucomatous retinal injury. Andrographolide (ADR) possesses antioxidant and neuroprotective activities, but its poor aqueous solubility and low bioavailability limit its therapeutic application. Here, we developed ADR-loaded poly(lactic-co-glycolic acid) nanoparticles (ADR-NPs) and evaluated their protective effects in oxygen-glucose deprivation/recovery (OGD/R)-injured R28 cells and a rat retinal ischemia/reperfusion (RIR) model. Network pharmacology implicated oxidative stress and programmed cell death pathways in the potential anti-glaucoma effects of ADR. ADR-NPs exhibited favorable physicochemical properties, sustained release, acceptable short-term stability, cytocompatibility. In OGD/R-injured R28 cells, both free ADR and ADR-NPs attenuated oxidative stress, mitochondrial membrane potential loss, and apoptosis-, pyroptosis-, and necroptosis-related alterations, with ADR-NPs providing greater overall protection at matched doses. In the RIR model, ADR-NP pretreatment preserved retinal structure, electrophysiological function, and RGC survival while reducing oxidative stress and retinal PANoptosis-related alterations. ADR-NPs also exhibited acceptable preliminary ocular and systemic tolerability. Collectively, ADR-NPs protect against experimental acute glaucomatous injury by attenuating oxidative stress, mitochondrial dysfunction, and PANoptosis-related alterations, while enhancing the cellular protective effects of ADR. Download: Download high-res image (124KB) Download: Download full-size image