Phagocytosis by retinal pigment epithelium and microglia does not affect vision restoration by P3HT nanoparticles in Retinitis pigmentosa

Photoreceptor degeneration in Retinitis pigmentosa (RP) is the most prevalent cause of inherited legal blindness, for which effective visual restoration treatments are still missing. Injectable prosthetic strategies represent a promising tool for vision restoration. We demonstrated that injectable poly(3-hexylthiophene) nanoparticles (P3HT-NPs) promote a sustained visual restoration in Royal College of Surgeons rats, an RP model harboring a mutation that impairs the phagocytic activity of the retinal pigment epithelium (RPE) and microglia, leading to progressive and combined rod/cone degeneration. However, it is unclear whether the efficacy of P3HT-NPs in this model is enhanced by the impairment of RPE and microglial phagocytosis, and thus whether this prosthetic intervention will also be effective in more typical forms of RP that primarily affect rods. Here, we evaluated the efficacy of P3HT-NPs in the pigmented retinal degeneration 10 (rd10) mouse, which carries a recessive missense mutation in the rod phosphodiesterase-6B gene, while retaining a morphologically and functionally intact RPE. We demonstrate that, in this mouse model of RP, P3HT-NPs restore visually driven responses at both subcortical and cortical levels at the end stage of photoreceptor degeneration. Although partial phagocytosis of P3HT-NPs by the RPE occurs, the P3HT-NPs remaining in the outer retina were sufficient to mediate a significant recovery of visual function characterized by complex light-dependent reactivation of the primary visual cortex and formation of implicit visual memories. These results demonstrate that healthy RPE and microglial activities do not compromise the efficacy of the injectable nanotherapeutic strategy, underscoring the clinical potential of P3HT-NPs for visual restoration in late-stage retinal degeneration, which closely mimics the conditions of RP patients undergoing prosthetic interventions.