An ROS-responsive, RGC-targeted nanotherapeutic strategy with a TRPV4 antagonist restores autophagic flux and protects RGCs in a rat model of chronic ocular hypertension

  • J Nanobiotechnology. 2026 Jun 17. doi: 10.1186/s12951-026-04661-2.
Jiarun Song  #  1 ,  Xueqi Zhang  #  2 ,  Pengwei Huang  1 ,  Hui Li  2 ,  Wenhui Liu  3 ,  Liyan Wang  4 ,  Ruiqing Wang  5 ,  Zhuoran Ye  1 ,  Jingxin Zhang  1 ,  Zhiyue Zhang  6 ,  Hui Guo  7
Affiliations
  • 1. Department of Ophthalmology, Qilu Hospital of Shandong University, Jinan, 250012, Shandong, China.
  • 2. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China.
  • 3. Tianjin Key Laboratory of Retinal Functions and Diseases, Tianjin Branch of National Clinical Research Center for Ocular Disease, Eye Institute and School of Optometry, Tianjin Medical University Eye Hospital, Tianjin, 300384, China.
  • 4. Electron Microscopy Laboratory, School of Basic Medical Sciences, Shandong University, Jinan, 250012, Shandong, China.
  • 5. Cheeloo College of Medicine, Qilu Hospital of Shandong University, Shandong University, Jinan, 250012, Shandong, China.
  • 6. State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, Key Laboratory of Chemical Biology (Ministry of Education), Shandong Key Laboratory of Targeted Drug Delivery and Advanced Pharmaceutics, School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, 250012, Shandong, China. [email protected].
  • 7. Department of Ophthalmology, Ruijin Hospital, Shanghai Jiao Tong University, Shanghai, 200025, China. [email protected].
  • # Contributed equally.
PMID: 42310662 DOI: 10.1186/s12951-026-04661-2
Abstract

Background: Glaucoma leads to progressive degeneration of retinal ganglion cells (RGCs), highlighting an urgent need for neuroprotective strategies beyond intraocular pressure reduction. Our previous work demonstrated that activation of the mechanosensitive channel Transient Receptor Potential Vanilloid 4 (TRPV4) contributes to RGC Apoptosis in a chronic ocular hypertension (COH) rat model, and that the TRPV4 antagonist HC-067047 exhibits neuroprotective potential. However, its mechanism of action remains unclear, and its therapeutic efficacy is limited by poor RGC targeting, rapid clearance, and associated toxicity.

Results: In this study, we developed an RGC-targeted and Reactive Oxygen Species (ROS)-responsive drug delivery system by combining cholera toxin subunit B (CTB)-mediated selective uptake with an ROS-cleavable polymeric shell encapsulating HC-067047. The nanoparticles were efficiently internalized by RGCs and released the drug specifically in the COH-induced high-ROS microenvironment. Mechanistically, COH-induced TRPV4 activation led to calcium dysregulation and impaired autophagic flux-a key process linked to RGC vulnerability. Inhibition of TRPV4 via this targeted delivery system restored autophagic flux and significantly reduced COH-induced RGC injury.

Conclusions: These findings identify TRPV4-mediated Autophagy dysregulation as a critical mechanism in glaucomatous damage and propose a precise, controlled-release nanotherapeutic strategy for the treatment of glaucoma.

Keywords
Autophagy; Glaucoma; Nanoparticles; Retinal ganglion cells; TRPV4.
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