A natural product-based pH-responsive hydrogel nanoplatform for ulcerative colitis therapy via synchronous regulation of immune microenvironment and intestinal barrier.

Ulcerative colitis (UC) is a chronic relapsing disease characterized by the destruction of the intestinal epithelial barrier and dysregulation of immune homeostasis. Despite advancements in therapeutic strategies, current conventional treatments are often hampered by systemic side effects and variable responses. To address these issues, we innovatively developed a self-assembled hydrogel (BBH@PH) incorporating small-molecule phytochemicals (puerarin, berberine and baicalin). Specifically, BBH@PH possessed favorable mechanical strength and pH-sensitive swelling behavior as well as controlled drug release, with less than 20% drug leakage in simulated gastric fluid and over 75% cumulative release in simulated colonic fluid. Moreover, this gel exhibited effective ROS-scavenging activity and modulation of macrophage polarization toward the M2 phenotype in living cells. Subsequent investigations into its protective effects on the intestinal barrier revealed that BBH@PH efficiently alleviated LPS-induced damage in Caco-2 monolayers, preserved the integrity of intercellular tight junctions and facilitated epithelial cell wound healing. In vivo, this gel achieved prolonged gastrointestinal retention (1.60-fold higher than that of free ICG at 24 h) and enhanced transepithelial absorption (3.10-, 1.92- and 4.02-fold increases compared to free berberine, baicalin, and puerarin, respectively). Benefiting from its unique properties, BBH@PH significantly suppressed the secretion of pro-inflammatory cytokines and M1 macrophage polarization, upregulated the expression of intestinal tight junction proteins and rebalanced the dysregulated intestinal microbiota in DSS-induced colitis mice. Notably, the absence of toxic manifestations indicated a favorable safety profile for BBH@PH. Overall, these findings present an innovative therapeutic option for UC, underscoring the synergistic effects of phytochemicals.