Abstract
<title>Abstract</title> <p>Age-related macular degeneration (AMD) causes irreversible vision loss via progressive degeneration of the retinal pigment epithelium (RPE) and photoreceptors. RPE transplantation is a promising therapeutic approach for retinal degeneration, yet immune-mediated graft rejection severely impairs its clinical efficacy. Microglia/macrophage M1/M2 polarization dominates the post-transplantation immune microenvironment and critically determines graft survival. Here, we investigated whether the Schistosoma japonicum-derived peptide SjDX5-271 modulates innate immune polarization to improve RPE transplantation outcomes. mCherry-labeled human fetal RPE (fRPE) cells were transplanted into the subretinal space of sodium iodate-induced retinal degenerative mice. In vitro primary microglia, together with in vivo intravitreal administration, were used to verify SjDX5-271 immunomodulatory effects via flow cytometry, immunofluorescence and qPCR. Retinal structural repair and visual functional recovery were evaluated by histology and electroretinography (ERG). Subretinal fRPE transplantation triggered time-dependent innate immune activation, with microglia/macrophage M1 activation peaking at day 7 and gradual graft loss starting at day 3. Optimized 100 µg/mL SjDX5-271 efficiently shifted microglia/macrophage polarization toward the M2 anti-inflammatory phenotype, suppressed M1 proinflammatory responses, and improved graft survival without disturbing systemic immune homeostasis. Combined SjDX5-271 treatment and fRPE transplantation restored retinal structure, preserved outer nuclear layer thickness, elevated scotopic ERG amplitudes, and improved visual function. In conclusion, SjDX5-271 locally remodels the post-transplantation immune microenvironment by inducing M2 polarization, thereby enhancing RPE graft survival, integration and visual recovery. This targeted immunomodulatory strategy provides a promising adjunctive therapy for AMD and retinal degenerative cell therapy.</p>