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

Abstract

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.