Inflammation-Triggered Self-Immolative Conjugates Enable Oral Peptide Delivery by Overcoming Gastrointestinal Barriers

Plain-language summary

Published in Science Advances in 2025, this study used the tripeptide KPV (Lys-Pro-Val) as a model anti-inflammatory peptide to develop an inflammation-responsive amphiphilic prodrug system (proKPV) designed to survive gastrointestinal conditions. While free KPV completely lost its ability to inhibit pro-inflammatory cytokine production after exposure to GI conditions, proKPV maintained potent anti-inflammatory activity and significantly reduced TNF-α, IL-6, and IL-1β in LPS-activated macrophages more effectively than free KPV. In vivo studies in DSS-induced colitis mice confirmed that oral proKPV enabled efficient intestinal barrier penetration, systemic absorption, and preferential targeting to inflamed tissues with prolonged retention.