Advances in oral treatment of inflammatory bowel disease using protein-based nanoparticle drug delivery systems.

Inflammatory bowel disease (IBD) comprises chronic autoimmune disorders with significant morbidity, highlighting the need for advanced, noninvasive, targeted therapies. Protein-based nanoparticle drug delivery systems (PNP-DDSs) have emerged as promising platforms to overcome limitations of conventional IBD therapies by improving drug stability and bioavailability while enabling colon-specific delivery. This review systematically classifies PNP-DDSs derived from natural proteins (albumin, gelatin, silk fibroin, and plant-derived proteins) and discusses their design principles along with strategies for intestinal targeting, including particle size and surface charge modulation, stimuli-responsive release (triggered by pH, reactive oxygen species, or enzymes), and active targeting. It highlights recent preclinical advances with oral PNP-DDSs delivering curcumin, resveratrol, 5-aminosalicylic acid, quercetin, and other anti-inflammatory agents, which demonstrate the therapeutic potential of these nanoplatforms in IBD models. Despite promising preclinical outcomes, clinical translation of PNP-DDSs remains challenging due to patient heterogeneity, manufacturing scale-up difficulties, and safety concerns. Future progress will require interdisciplinary innovation and optimization of multi‑stimuli-responsive designs for precise and safe clinical application of PNP-DDSs in IBD management.