Although the eradication of Helicobacter pylori is critical for preventing gastric cancer, current therapies often overlook the restoration of the gastric microenvironment, leading to a prevalence of delayed tissue healing and dysbiosis. Consequently, many patients remain in a persistent pathological state despite successful H. pylori clearance, presenting a major bottleneck in clinical treatment. This review summarizes recent advancements in gastric-targeted drug delivery systems, illustrating the evolution from a singular antibacterial approach to an integrated sequential strategy encompassing clearance, repair, and homeostasis reconstruction. We examine smart gastro-retentive and nanodelivery systems designed to overcome physiological barriers, highlighting formulations that extend gastric residence time and maintain local drug concentrations above the Minimum Inhibitory Concentration for prolonged periods. Furthermore, we discuss spatiotemporally controllable biomaterials, such as Janus hydrogels and ROS-responsive carriers. These systems demonstrate distinct pH-dependent release kinetics and high stability in simulated gastric fluids, effectively preserving bioactive payloads to modulate the immune microenvironment. By facilitating the transition from pro-inflammatory to anti-inflammatory phenotypes, these biomaterials support epithelial regeneration. The review concludes with an analysis of postbiotics and the proposed holistic strategy, offering a promising therapeutic framework for mitigating the inflammation-to-cancer transition and promoting gastric health remodeling.

Inflammatory bowel disease (IBD) is characterized by intestinal barrier dysfunction and excessive inflammation, in which STAT3 signaling plays a critical role. Berberine is clinically effective against colitis; its application is limited by low bioavailability and toxicity. Berberrubine, a major metabolite of berberine, exhibits improved pharmacological properties; however, its therapeutic potential in IBD remains unclear. The efficacy and mechanisms of berberine and berberrubine were evaluated in DSS-induced colitis mice, LPS-stimulated cells and intestinal organoids. STAT3 knockout cell lines were generated using CRISPR-Cas9 to assess the role of STAT3 in mediating the pharmacological activities of both compounds. We found that berberrubine significantly alleviated colitis, reduced pro-inflammatory cytokines (IL-6 and TNF-α), and restored intestinal barrier integrity by upregulating ZO-1 and claudin-1 in vivo and in organoids, demonstrating superior efficacy and safety to berberine. Mechanistically, both compounds inhibited STAT3 activation and nuclear translocation. STAT3 deficiency attenuated their anti-inflammatory, anti-tumor, and barrier-protective effects. Notably, berberrubine exhibited selective cytotoxicity to cancer cells over normal epithelial cells, suggesting a favorable therapeutic window. Collectively, berberrubine ameliorates intestinal barrier dysfunction and inflammation through inhibition of the STAT3 signaling pathway. Its superior efficacy and favorable safety profile compared to berberine support its potential as a novel therapeutic agent for IBD.