Endogenous dual stimuli-activated NO generation in the conventional outflow pathway for precision glaucoma therapy

High intraocular pressure (IOP) has been regarded as a predominant risk factor for glaucoma. Nitric oxide (NO) is shown to lower IOP, but the magnitude and duration of IOP reduction are not satisfying due to the poor cornea penetration of NO drugs and limited NO generation in the trabecular meshwork (TM)/Schlemm's canal (SC) area. Herein, we introduce deep cornea penetrating biodegradable hollow mesoporous organosilica (HOS) nanocapsules for the efficient co-delivery of hydrophobic JS-K (J_R) and hydrophilic l-Arginine (L_O). The resulting HOS-J_RL_O can be reduced and oxidized by the ascorbic acid (AA) and catalysis of endothelial nitric oxide synthase (eNOS) in the TM/SC microenvironment to release NO for inducing appreciable IOP reduction in various glaucoma mouse models. In addition to developing an endogenous stimuli-responsive NO nanotherapeutic, this study is also expected to establish a versatile, non-invasive, and efficacious treatment paradigm for precision glaucoma therapy.