Food-derived β-lactoglobulin nanofibrils: An efficacy, safe, and scalable solution to overcome oral insulin delivery challenges

Oral delivery of biologics presents a formidable challenge: achieving high bioavailability without compromising gastrointestinal barrier integrity or clinical scalability—a trilemma that remains unaddressed by existing chemical permeation enhancers, ligand-modified nanoparticles, or exosome platforms. Here, we repurpose β-lactoglobulin (BLG) nanofibrils that resolve this challenge through a unique “enhance-degrade-restore” mechanism. In vivo, these nanofibrils enable oral insulin bioavailability reaching 10.2–12.3 %, and long-term safety studies confirm the absence of intestinal damage. Mechanistic studies reveal that the nanofibrils facilitate Ca 2+ influx-induced calpain activation to enhance paracellular permeability, followed by protease-mediated degradation that ensures timely restoration of barrier integrity. Moreover, nanofibrils maintain full adjuvant activity when integrated into commercial milk products, highlighting their formulation flexibility and robustness. This work introduces a sustainable “waste-to-nanomedicine” strategy that unites high-efficiency peptide delivery with environmentally responsible nanomaterial design. • Fibrilization converts whey into an oral insulin delivery platform that overcomes the bioavailability-safety-scalability challenge. • Nanofibrils enhance permeability via calpain activation and are cleared by proteases to restore the intestinal barrier integrity. • Nanofibrils enable oral insulin bioavailability reaching 10.2–12.3 % in diabetic mice. • An 18-month dietary intervention with nanofibrils shows no safety issues.