Dendrimer-targeted immunosuppression of microglia reactivity super-accelerates photoreceptor regeneration in the zebrafish retina

Abstract Retinal regeneration occurs naturally in zebrafish but not in mammals. A thorough understanding of the mechanisms regulating regeneration may help to advance strategies for stimulating retinal repair in humans. We previously implicated microglia as key regulators of retinal regeneration using a zebrafish model of inducible photoreceptor degeneration. Intriguingly, post-injury treatments with the immune suppressant dexamethasone (Dex) resulted in accelerated photoreceptor regeneration. Modifying microglia responses to retinal cell death may therefore promote neuroregenerative processes. Here, we investigated the effect of Dex on microglia reactivity in the regenerating zebrafish retina using adaptive optics-corrected lattice light-sheet microscopy. Quantitative analysis of in vivo time-lapse imaging data revealed that Dex inhibited microglia migration speed, consistent with an immunosuppressive effect. Unfortunately, long-term treatment with glucocorticoids, including Dex, causes adverse side effects which limits their use therapeutically. To overcome this limitation, a nanoparticle-based drug delivery strategy was used to target Dex to reactive microglia. We show that conjugating Dex to dendrimer nanoparticles: 1) dramatically decreased toxicity in larval zebrafish, 2) succeeded in selective targeting of reactive microglia and, 3) resulted in “super-accelerated” photoreceptor regeneration kinetics. These data support the use of dendrimer-based drug formulations for modulating microglia reactivity in degenerative disease contexts, especially as therapeutic strategies for promoting regenerative responses to neuronal cell loss.