Acid-enhanced drinkable hydrogel co-delivering riboflavin-loaded nanozymes for orchestrated inflammation-immune modulation and redox homeostasis in colitis therapy.

Conventional inflammatory bowel disease therapies are limited by inefficient colon-targeted delivery, systemic side effects, and a failure to rectify the underlying oxidative stress and immune dysregulation. Riboflavin (RAF) possesses ideal antioxidant and immunomodulatory properties for colitis therapy but suffers from rapid proximal absorption. While acid-degradable metal-organic framework (MOF) nanozymes can co-deliver RAF and catalytically eliminate reactive oxygen species (ROS), they lack colon-retentive capacity. To overcome these barriers, we engineered an acid-enhanced, drinkable hydrogel for the coordinated delivery of riboflavin-loaded Pt-MOF nanozymes (RAF@Pt-ZIF@CS, RPZCS). This food-grade sodium alginate system undergoes a drinkable sol-to-mucoadhesive gel transition triggered specifically by the acidic colonic microenvironment (pH 5.0-6.0). The subsequent acid-etching of the Pt-MOF framework enables spatiotemporally coupled burst release of RAF and Pt ions. In a DSS-induced colitis model, RPZCS demonstrated superior lesion retention and exerted comprehensive therapeutic effects. It robustly scavenged ROS via the SCAD-DJ-1-KEAP1-Nrf2 pathway, suppressed pro-inflammatory M1 macrophage polarization, rebalanced the Treg/Th17 immune axis and pro-/anti-inflammatory cytokines, enhanced mucosal/epithelial barrier integrity and restore gut microbiota. Furthermore, RPZCS favorably remodeled the gut microbiota structure. A 14-day repeated-dose toxicity study confirmed its "drinkable-grade" safety. Collectively, this acid-responsive hydrogel platform achieves orchestrated inflammation-immune modulation and redox homeostasis, offering a safe, effective, and highly compliant oral strategy for targeted colitis therapy.