Alkaline phosphatase-responsive hydrogel for efficient management of autoimmune intraocular inflammation

Autoimmune uveitis (AU) remains a leading cause of visual impairment and blindness worldwide, necessitating efficient and innovative therapeutic strategies to overcome the limitations of current clinical interventions. Capitalizing on the significant elevation of alkaline phosphatase (ALP) levels in intraocular tissues (vitreous humor, retina) during AU pathogenesis, we rationally designed an ALP-responsive self-delivering dexamethasone sodium phosphate (DexP) hydrogel using an ionic cross-linking approach. This DexP hydrogel serves as a sustained-release depot for adalimumab (ADA), enabling synergetic AU therapy through a simple combination of aqueous DexP and ADA solutions with calcium chloride under mild conditions, which facilitates controlled release of both therapeutics in an ALP-responsive manner. Importantly, in vivo experiments demonstrated that a single intravitreal (IVT) injection of ADA@DexP hydrogel significantly attenuated autoimmune intraocular inflammation by effectively inhibiting inflammatory cell infiltration, suppressing pro-inflammatory cytokines (IL-17A, IL-1β, TNF-α), and preserving blood-retinal barrier (BRB) integrity. Furthermore, the intravitreal administration of ADA@DexP hydrogel exhibited excellent intraocular biocompatibility and a safety profile. Overall, this carrier-free ADA@DexP hydrogel represents a promising alternative strategy for AU therapy, particularly given that both DexP and ADA are FDA-approved clinical agents.