Hesperidin-Loaded Nanoparticles Attenuate Pathological Angiogenesis in Oxygen-Induced Retinopathy by Modulating the...

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.