Inflammation-responsive sodium alginate-based microalgal hydrogel with pH/ROS dual sensitivity for oral colon-targeted therapy of ulcerative colitis.

Ulcerative colitis (UC) is associated with epithelial barrier disruption, oxidative stress, inflammation, and gut microbiota dysbiosis. Oral colon-localized delivery remains challenging because therapeutic cargos must resist gastric exposure, avoid premature release, be retained at inflamed colonic sites, and respond to pathological microenvironments. Herein, a pH/reactive oxygen species (ROS) dual-responsive calcium alginate microalgal hydrogel, denoted SP@GaTa@ALG (SGA), was developed for localized UC therapy. Gallium-tannic acid nanoparticles (GaTa NPs) were loaded onto Spirulina (SP) and encapsulated within a Ca2+-crosslinked alginate matrix. The calcium alginate network provided gastric protection and pH-dependent control over Ga3+ diffusion, while GaTa enabled ROS-responsive Ga3+ release and antioxidant activity. In vitro, SGA scavenged free radicals, reduced intracellular ROS accumulation, protected epithelial cells against H2O2-induced injury, preserved mitochondrial membrane potential, and promoted an anti-inflammatory-like macrophage phenotype. After oral administration, SGA showed prolonged gastrointestinal retention and enhanced colonic localization compared with non-encapsulated SP@GaTa (SG). In dextran sulfate sodium (DSS)-induced colitis mice, SGA alleviated body-weight loss, reduced disease activity, restored colon length, improved zonula occludens-1 (ZO-1) and Occludin expression, suppressed inflammatory mediators, and was associated with gut microbiota remodeling. These findings support SGA as a traceable, carbohydrate-polymer-based oral platform for inflammation-responsive UC intervention.