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.