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. RPZCS, an acid‑enhanced drinkable hydrogel, undergoes colonic microenvironment‑triggered sol‑to‑mucoadhesive gel transition for targeted delivery of riboflavin and Pt ions, scavenges reactive oxygen species via the SCAD‑DJ‑1–KEAP1–Nrf2 pathway, rectifies immune imbalance, restores intestinal barrier integrity and gut microbiota, thereby alleviating DSS‑induced colitis.