Clodronate liposome effectively mitigates chemically-induced retinal pigment epithelium toxicity

Minocycline treatment fails to ameliorate NaIO 3 - and MNU-induced retinal degeneration. • Depletion of resident retinal microglia by PLX3397 does not alleviate photoreceptor apoptosis in either model. • Clodronate liposome treatment ameliorates NaIO 3 -induced retinal pigment epithelium (RPE) toxicity. Visual impairment resulting from accidental chemical exposure is commonly encountered in emergency medicine, yet effective clinical interventions remain lacking. Given the critical roles of both resident microglia and peripheral macrophages in retinal degenerative diseases, this study systematically evaluated the protective effects of minocycline, PLX3397, and clodronate liposomes in sodium iodate (NaIO 3 )- and N-methyl-N-nitrosourea (MNU)-induced retinal degeneration models. Suppression of microglial activation with minocycline or depletion of resident microglia with PLX3397 failed to ameliorate retinal damage in either model, as evidenced by persistent fundus atrophy, diminished electroretinogram responses, and robust photoreceptor apoptosis. In contrast, systemic depletion of peripheral macrophages using clodronate liposomes significantly alleviated fundus atrophy, partially preserved visual function, and increased photoreceptor and retinal pigment epithelium (RPE) survival in the NaIO 3 model, but conferred no protection in the MNU model. These findings suggest that clodronate liposomes exert model-dependent protection, likely through modulation of peripheral macrophage-mediated RPE toxicity following chemical exposure.