Oral Protein Fibril Microgels with Gastric Stability and Intestinal Targeting Enhance Capsaicin Bioavailability for Effective Obesity Prevention.

To address the susceptibility of protein fibrils to pepsin degradation, this study proposed a fibril-to-microgel hierarchical assembly strategy, where flexible whey protein isolate fibrils (WPIF) and rigid flaxseed protein isolate fibrils (FPIF) were in situ self-cross-linked into microgels via a W/O emulsion template, followed by capsaicin (Cap) loading. Both microgels exhibited high gastric stability and intestinal response release properties. Compared with WPIF-based microgels (WPIFM), FPIF-based microgels (FPIFM) exhibited a more sustained intestinal digestion profile, leading to a higher Cap bioavailability. In high-fat-diet-induced obese mice, Cap-loaded microgels (WPIFM/Cap and FPIFM/Cap) effectively prevented metabolic disorders, as evidenced by reduced lipid accumulation, hepatic steatosis, and pro-inflammatory cytokines, with FPIFM/Cap demonstrating the highest protective efficacy. Both microgels modulated gut microbiota homeostasis, with FPIFM/Cap uniquely enriching Akkermansia, potentially due to its high arginine content and its stable fibrillar structure. This work provides a proof of concept for upcycling agricultural processing byproduct proteins into high-performance biomaterials for mitigating metabolic diseases.