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

  • Theranostics. 2026 Jan 1;16(2):830-851. doi: 10.7150/thno.112836.
Shuhan Meng  1  2  3  4 ,  Weizhou Fang  1  2  3  4 ,  Yukun Wu  1  2  3  4 ,  Zhaohua Xia  1  2  3  4 ,  Tiansheng Chou  5  4 ,  Yang Xia  5  4 ,  Lexi Ding  1  2  3  4 ,  Xuezhi Zhou  1  2  3  4 ,  Xiaobo Xia  1  2  3  4
Affiliations
  • 1. Eye Center of Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
  • 2. Hunan Key Laboratory of Ophthalmology, Changsha, Hunan, 410008, P. R. China.
  • 3. National Clinical Key Specialty of Ophthalmology, Changsha, Hunan, 410008, P. R. China.
  • 4. National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
  • 5. National Medical Metabolomics International Collaborative Research Center, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, P. R. China.
PMID: 41346714 DOI: 10.7150/thno.112836
Abstract

Rationale: 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. Methods: 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 in vitro using an oxygen-glucose deprivation/reperfusion (OGD/R) R28 cell model and in vivo using a RI/R rat model. Results: 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. Conclusion: 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.

Keywords
PANoptosis; glaucoma; melatonin; nanoparticle; retinal ganglion cell.
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