Noninfectious uveitis (NIU) is a common subtype of uveitis characterized by autoinflammatory or autoimmune processes primarily mediated by Th1/Th17 cells [1], [2], [3], [4], [5]. If inadequately managed, NIU can significantly impair visual function and ultimately lead to blindness [6], [7], [8]. Current treatment strategies for NIU include glucocorticoids, immunosuppressants, and biological antibodies [9], [10], [11], with glucocorticoids remaining the cornerstone of therapy due to their potent inhibition of proinflammatory cytokine release [12], [13], [14], [15]. Nevertheless, prolonged systemic administration of glucocorticoids, particularly for uveitis affecting the middle and posterior ocular segments, frequently leads to substantial adverse effects [16], [17], [18], [19].

Over the past two decades, the Food and Drug Administration (FDA) has approved intravitreal glucocorticoid injections as well as short- and long-acting implants aimed at delivering medication directly to posterior eye tissues, thus reducing administration frequency. While these innovations have improved therapeutic precision, they carry significant limitations, including procedural discomfort, subconjunctival hemorrhage, and high costs associated with surgical implantation [20], [21], [22], [23], [24], [25], potentially restricting patient access. Therefore, there remains an urgent unmet need for noninvasive, safer, cost-effective, and patient-friendly therapeutic alternatives, particularly in the form of eye drops.

Topical drug administration faces significant challenges, such as poor water solubility, rapid tear turnover, and ocular membrane barriers, collectively resulting in low bioavailability—typically ranging from 0.07 % to 4 % in the aqueous humor, and less than 0.001 % reaching the retina [26]. To overcome these limitations, innovative drug delivery systems (DDS), including emulsions, nano-micelles, in-situ gels, liposomes, nanoparticles, and cyclodextrin (CD) aggregates, have been developed [27], [28], [29], [30], [31]. Among these, dexamethasone (DEX)-loaded γ CD aggregates (suspension eye drops) have progressed to Phase III clinical trials for retro-ocular diseases, demonstrating promising efficacy, particularly in the treatment of diabetic macular edema.

Cyclodextrins, characterized by a hydrophilic outer surface and a hydrophobic inner cavity, can encapsulate lipophilic drugs, thereby enhancing their water solubility [32], [33]. Natural cyclodextrins also possess strong self-aggregation properties, forming micron-sized aggregates that improve drug delivery efficiency [34]. Among these, γ-cyclodextrin (γ-CD) stands out due to its larger internal cavity, reduced toxicity, and unique ability to be hydrolyzed by human α-amylase [35]. When applied topically, drug/γ-CD microparticles initially remain on the ocular surface before dissociating into nanoparticles, which facilitate drug permeation through mucus layers and enhance diffusion into posterior ocular tissues [36]. However, despite the promise of DEX suspension eye drops, clinical trials report that 20–30 % of patients experience elevated intraocular pressure, increasing the risk of cataracts and glaucoma.

Recent studies have shown that gallic acid (GA), a naturally occurring phenolic compound [37], has strong antioxidant stress capacity by eliminating reactive oxygen species [38], [39], Meanwhile, it may protect corneal epithelial cells and reduce intraocular pressure [40]. We hypothesized that GA could synergize with dexamethasone (DEX) to improve the treatment of noninfectious uveitis (NIU). While γ-cyclodextrin (γ-CD) can encapsulate both DEX and GA, GA’s high hydrophilicity limits its penetration across lipophilic ocular barriers. To overcome this challenge, we synthesized a novel prodrug, dexamethasone gallate (DG), which combines the anti-inflammatory properties of DEX with the antioxidant effects of GA. Our findings reveal that DG-loaded CD suspension eye drops effectively inhibit pro-inflammatory factors and oxidative stress, significantly reducing ocular inflammation in an experimental autoimmune uveitis (EAU) model of NIU. Importantly, DG suspensions not only reduced intraocular pressure but also provided a safe and effective therapeutic option for NIU.