Hesperidin-Loaded Nanoparticles Attenuate Pathological Angiogenesis in Oxygen-Induced Retinopathy by Modulating the Retinal Immune Microenvironment

Retinal neovascularization is closely linked to retinal inflammation. Microglia, the resident immune cells of the retina and the primary responders to inflammatory stimuli, play a central role in pathological retinal vascular remodeling, including aberrant neovascularization and increased vascular tortuosity. High-mobility group box 1 (HMGB1), a ubiquitously expressed DNA-binding protein, functions as a damage-associated molecular pattern and has been shown to drive microglial polarization toward the pro-inflammatory M1 phenotype. Whereas M1 microglia exacerbate inflammatory responses, M2 microglia exhibit anti-inflammatory and tissue-repair functions. Accordingly, inhibition of HMGB1 to induce metabolic reprogramming of microglia may promote the transition from the M1 to the M2 phenotype. In this study, we adopted a targeted therapeutic strategy aimed at modulating the M1/M2 polarization balance of microglia to attenuate retinal inflammation and suppress pathological angiogenesis, thereby offering a potential treatment for retinal neovascularization. To achieve this, we engineered a self-assembled nanoparticle delivery system (H–H@MG1) designed to selectively target M1 microglia. These nanoparticles encapsulate the anti-inflammatory flavonoid hesperidin and are functionalized with an M1 microglia-targeting peptide (MG1). In vitro experiments demonstrated that H–H@MG1 efficiently targets M1 microglia, inhibits HMGB1-induced activation of resting microglia, and promotes their polarization toward the M2 phenotype. Furthermore, in vivo studies using an oxygen-induced retinopathy mouse model revealed that H–H@MG1 rebalances M1/M2 microglial polarization within the retina, remodels the retinal immune microenvironment, and significantly reduces the expression of pro-inflammatory cytokines, including IL-6 and TNF-α. Collectively, these effects suppress abnormal retinal vascular remodeling and pathological angiogenesis. Overall, this nanodelivery system effectively reshapes the retinal immune microenvironment and represents a promising therapeutic strategy for the treatment of retinal neovascularization.