Superoxide-responsive mitochondria-targeting peptide-persulfide donor conjugate for retinal ganglion cells protection in glaucoma

Glaucoma is a leading cause of irreversible blindness, primarily due to the progressive degeneration of retinal ganglion cells (RGCs). Despite available treatments targeting intraocular pressure (IOP), there remains an urgent need for effective strategies that directly protect RGCs by addressing mitochondrial dysfunction and oxidative stress—two interlinked pathological hallmarks of glaucomatous neuropathy. Here, we report the development of Mitochondria-Targeting Reactive Persulfide Donor Peptide (RPDP-Mito), a superoxide-responsive, mitochondria-targeting peptide-persulfide donor conjugate, designed to overcome the limitations of conventional hydrogen sulfide (H 2 S) therapies. By integrating a triphenylphosphine (TPP) targeting moiety and a superoxide-responsive persulfide donor (SOPD), RPDP-Mito enables controlled, subcellular release of persulfide/H 2 S specifically within stressed mitochondria. RPDP-Mito exhibits excellent biocompatibility and sustained antioxidative activity in both in vitro RGC models and in vivo chronic ocular hypertension (COH) models. It significantly reduced reactive oxygen species (ROS) accumulation, preserved mitochondrial integrity, suppressed RGC apoptosis, and improved electrophysiological function. Compared to conventional H 2 S donors, RPDP-Mito demonstrated superior mitochondrial localization and neuroprotective efficacy. This study presents RPDP-Mito as a novel therapeutic platform that addresses a long-standing challenge in glaucoma treatment: targeted and responsive delivery of redox-active compounds to RGC mitochondria. Our findings support the potential of RPDP-Mito to shift the paradigm from IOP control to mitochondrial-centered neuroprotection in glaucomatous neuropathy.