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.

高眼压（IOP）被认为是青光眼的主要危险因素。一氧化氮 (NO) 显示可降低 IOP，但由于 NO 药物的角膜渗透性差和小梁网 (TM)/施累姆氏管 (SC) 区域中 NO 生成有限，因此降低 IOP 的幅度和持续时间并不令人满意。在此，我们引入了可穿透深角膜的可生物降解中空介孔有机二氧化硅 ( HOS) 纳米胶囊，用于有效共同递送疏水性 JS-K (J _R ) 和亲水性l -精氨酸 (L _O )。由此产生的 HOS-J _R L _O在 TM/SC 微环境中，可以通过抗坏血酸 (AA) 和内皮型一氧化氮合酶 (eNOS) 的催化还原和氧化，以释放 NO，从而在各种青光眼小鼠模型中诱导明显的眼压降低。除了开发一种内源性刺激响应性 NO 纳米疗法外，该研究还有望为精准青光眼治疗建立一种多功能、无创且有效的治疗范式。