Reactive oxygen species/hypoxia dual-responsive polymers combined with melatonin inhibited PANoptosis of retinal ganglion cells for acute glaucoma treatment

<b>Rationale:</b> Acute glaucoma is triggered by sudden spikes in intraocular pressure, which induces retinal ischemia/reperfusion (RI/R), leading to hypoxia, oxidative stress, and ultimately PANoptosis in retinal ganglion cells (RGCs). Developing a therapeutic approach that simultaneously targets these events may offer a promising strategy for reducing secondary neuronal damage in acute glaucoma. <b>Methods:</b> We developed a reactive oxygen species (ROS)/hypoxia dual-responsive, biodegradable nanoparticle system (NPs) containing azo and thioketal bonds, designed to encapsulate melatonin (MT), a known endogenous antioxidant and PANoptosis inhibitor. The biocompatibility, biosafety, and therapeutic efficacy of MT-NPs were evaluated <i>in vitro</i> using an oxygen-glucose deprivation/reperfusion (OGD/R) R28 cell model and <i>in vivo</i> using a RI/R rat model. <b>Results:</b> The NPs efficiently released encapsulated MT in response to hypoxic conditions and the presence of ROS. This controlled-release system improved both the biocompatibility and long-term retention of MT in the retina. MT-NPs effectively alleviated hypoxia, cleared excess ROS, and inhibited PANoptosis in RGCs following acute glaucomatous injury. Compared to direct MT administration, MT-NPs were more effective at protecting RGC axons and somas and facilitating restoration of visual function in rats with acute glaucoma. <b>Conclusion:</b> This simplified but multifunctional delivery system leveraged the widely available and safe compound melatonin in a highly efficient nanoparticle platform. This system offers potent neuroprotective effects to the retina preventing injury caused by acute glaucoma, and thereby providing a promising clinically translatable strategy for the treatment of glaucoma.