Retinal hypoxia reversal with PLGA-oxygen nanobubbles

Pathologies associated with retinal hypoxia, including diabetic retinopathy, central/branch retinal artery occlusion (CRAO/BRAO), central/branch retinal vein occlusion (CRVO/BRVO), retinopathy of prematurity, sickle cell retinopathy, <i>etc</i>., have limited effective therapeutic intervention strategies. To address this shortcoming, herein we propose a biocompatible and biodegradable poly (lactic-<i>co</i>-glycolic acid) shell-based oxygen nanobubbles (PLGA-ONBs) platform, formulated with PLGA, polyvinyl alcohol (PVA), and NaHCO₃. The formulation of a novel PLGA-ONBs was proposed, and the synthesis process was optimized with respect to dependent (sonication power, PVA, and NaHCO₃ concentrations) and response (hydrodynamic diameter and oxygen capacity) variables. The optimized formulation has a concentration of (13.8 ± 0.01) × 10¹⁰ particles per ml with a hydrodynamic diameter of 142.83 ± 11.46 nm, and oxygen loading capacity of 47.2 ± 2.4 mg L^-1. After 4 weeks of storage, the ONBs were found to have an oxygen concentration of 38.9 ± 2.9 mg L^-1, indicating excellent oxygen retention capability. The PLGA-ONBs tested <i>in vitro</i> in Muller and R28 retinal cell lines demonstrated excellent biocompatibility and potential to mitigate hypoxia. In addition, the PLGA-ONBs treatment on hypoxic cells demonstrated restoration of mRNA expression of three key hypoxic genes (HIF-1α, PAI-1, and VEGF-A) to normoxic states, indicating hypoxia reversal potential. Biosafety of the PLGA-ONBs was demonstrated in a rabbit model, demonstrating promise in clinical translation. The PLGA-ONBs developed exhibited excellent oxygen loading and retention, potential in hypoxia mitigation, and a safety profile that could be a promising route to treating ischemic diseases of the eye.