Nanoencapsulated flavonoids for inflammatory bowel disease: a targeted approach toward clinical application

Abstract Flavonoids influence the composition of the intestinal microbiota, barrier integrity, and local immune responses, making them promising candidates for oral therapies in inflammatory bowel disease (IBD). However, their clinical use is limited by low solubility, molecular instability, and poor oral bioavailability, which hinder their ability to reach therapeutic levels at intestinal target sites, a limitation especially relevant in IBD, where delivering sufficient drug to the inflamed colonic mucosa is crucial. Nanoencapsulation is a promising, emerging solution, although the path to clinical use remains insufficiently established, largely due to the lack of a rational, target-driven design that translates nanoformulations into clinical outcomes. This Perspective introduces a design-focused framework that links formulation decisions to biological effects, microbiota impacts, and regulatory factors. It advances beyond previous reviews on nanoencapsulated flavonoids (Nano-Flav) or colon-targeted delivery, which primarily focused on encapsulation techniques and their characterization. By integrating four interdependent design pillars, it offers a prescriptive perspective intended to guide the rational design of flavonoid nanoformulations for clinical translation in IBD. We evaluate designs, regulatory issues, and preclinical models to advance these systems toward clinical practice. Biomaterial selection must account for gastrointestinal barriers, as site-specific release is guided by the interplay among gastrointestinal transit, luminal pH gradients, and microbiota enzymatic activity. The target-driven framework is structured on four interconnected pillars: molecular stability, site-specific activation, host-microbiota compatibility, and clinical translatability. We propose a roadmap for developing Nano-Flav, outlining experimental techniques and evidence-based elements to support personalized management of IBD.