Advances in nanomedicine-based retinal drug delivery: mechanisms and translational applications

Retinal diseases like age-related macular degeneration (AMD), diabetic retinopathy (DR), and diabetic macular edema (DME), alongside optic neuropathies such as glaucoma, are primary contributors to irreversible visual impairment and blindness, and not only impact the quality of life but also place considerable socioeconomic pressures on healthcare systems worldwide. Despite the availability of several therapeutic modalities, the clinical management of these conditions remains challenging due to the unique anatomical and physiological barriers of the eye (i.e., tear film, cornea, blood-aqueous barrier, and the blood-retinal barrier), which impede achieving therapeutic drug concentrations in the posterior segment. Topical administration exhibits low bioavailability, while systemic delivery is generally inefficient and associated with adverse effects. Intravitreal injections (IVIs) deliver drugs directly to the vitreous but necessitate frequent administration, hence increasing risks of endophthalmitis, retinal detachment, and patient non-compliance. Nanomedicine has revolutionized drug delivery science across various medical fields, offering significant advantages for therapeutic interventions. Nanoparticle (NP)-based systems enhance drug solubility and stability, improve pharmacokinetic profiles, facilitate passage across biological barriers, and enable targeted delivery to specific cells or tissues with surface modifications, thereby potentially increasing bioavailability while minimizing systemic toxicity. This review aims to illustrate recent advancements in the design principles, preclinical applications, and translational potential of NP-based drug delivery systems aimed at addressing the challenges inherent in treating posterior segment eye diseases. NPs (ranging from polymeric and lipid-based systems to inorganic and hybrid forms) have been able to effectively carry various formulations of antiangiogenic, anti-inflammatory, anti-neoplastic, and antioxidant compounds, as well as genetic materials, to counteract such disorders. NP's size, surface charge, and composition can be modulated to optimize interaction with ocular tissues and overcome barriers. With their controlled and sustained drug release, NPs decrease the required frequency of IVIs. In addition, NPs can encapsulate a wide range of therapeutic agents (including hydrophobic molecules, proteins, and nucleic acids) and are amenable to the functionalization of their surfaces with ligands for specific receptors on retinal cells, thereby enhancing therapeutic efficacy and minimizing local toxicities. The findings of this review will establish a research agenda for translating NP-based interventions into clinical practice.