Drug Delivery Across the Blood-Retinal Barrier: Biological Gateways for Posterior Segment Therapy.
Posterior-segment retinal diseases remain a leading cause of irreversible vision loss worldwide, yet effective treatment continues to be limited by the challenge of achieving sufficient and durable drug exposure within target ocular tissues. Although intravitreal injection has transformed the management of retinal diseases, therapeutic success is determined not only by drug potency but also by transport across retinal interfaces, intraocular distribution, and long-term tissue exposure. Traditionally, these challenges have been attributed primarily to the restrictive nature of the blood-retinal barrier (BRB). In this review, we propose a shift from a barrier-centric view of ocular drug delivery toward a biological gateway framework. We examine how the inner and outer BRB actively regulate therapeutic access through coordinated mechanisms including paracellular restriction, transcellular transport, receptor-mediated trafficking, and disease-associated remodeling. Building upon this biological foundation, we discuss how route-specific delivery strategies-including systemic, intravitreal, suprachoroidal, and subretinal administration-interact with distinct BRB interfaces and influence therapeutic exposure. We further review clinically established and emerging delivery platforms, including sustained-release implants, refillable port-based systems, gene-based therapies, hydrogels, polymeric and lipid-based carriers, biomimetic systems, inorganic and hybrid nanomaterials, and stimulus-responsive platforms. Particular emphasis is placed on how material properties, pharmacokinetic behavior, and biological interactions collectively determine drug localization, retention, and efficacy. Finally, we discuss disease-adaptive delivery systems, cell-specific targeting, quantitative exposure modeling, and translational challenges that influence clinical implementation. By integrating retinal biology, pharmacokinetics, materials science, chemistry, and clinical ophthalmology, this review provides a gateway-centered framework for the rational design of next-generation drug delivery strategies for posterior-segment diseases.