An ROS-Responsive, RGC-Targeted Nanotherapeutic Strategy with a TRPV4 Antagonist Restores Autophagic Flux for Glaucomatous Neurodegeneration

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.