Triple-emulsion microfluidic Core–Shell hydrogel microcapsules for oral pentoxifylline Delivery: Ameliorating colitis and rebalancing gut microbiome

Inflammatory bowel disease (IBD) encompasses chronic or relapsing inflammation within different regions of the gastrointestinal tract. Pentoxifylline (PTX) , a methylxanthine derivative primarily used to improve blood flow in peripheral vascular diseases, has demonstrated anti-inflammatory and immunomodulatory properties, suggesting its potential in attenuating IBD-associated inflammation. However, its clinical application in IBD remains limited, partly due to its short half-life and poor targeting to inflamed intestinal tissues, necessitating strategies to enhance its bioavailability and tissue-specific delivery. To address this limitation, we developed a targeted drug delivery system utilizing a microfluidic approach to fabricate pH-responsive core–shell hydrogel microcapsules encapsulating PTX, referred to as PTX-loaded hydrogel microcapsules (PHM), for enhanced delivery to inflamed colonic tissue. These microcapsules were generated via photopolymerization of triple emulsion droplets, resulting in a structure composed of a poly(acrylic acid)-poly(ethylene glycol) diacrylate (PAA–PEGDA) shell and a PEGDA core, separated by a thin oil layer. The oil layer serves as a protective barrier against the acidic gastric environment, while the pH-responsive swelling of the PAA–PEGDA shell at basic pH (7.5) compresses and destabilizes the oil layer, thereby enabling controlled PTX release specifically in the colonic environment. In vivo studies using dextran sulfate sodium (DSS)-induced IBD in ICR mice demonstrate that PHM significantly mitigates disease severity, as evidenced by an approximately 38.5% reduction in disease activity index scores, restoration of mucosal architecture, and decreased infiltration of colonic macrophages. In parallel, PHM treatment markedly suppresses colonic inflammatory responses, lowering IL-1β by 40%, IL-6 by 66.2%, and TNF-α by 36.2% compared to DSS-treated mice, along with a broader reduction of pro-inflammatory mediators, highlighting its anti-inflammatory potential. Notably, PHM also contributes to the rebalancing of dysbiotic gut microbiota, including the restoration of beneficial genera such as Bacteroides acidifaciens and PAC001120_s , thereby promoting microbial homeostasis. Collectively, these findings underscore PHM as a promising PTX-based therapeutic strategy for effective IBD intervention.