Inflammation-triggered self-immolative conjugates enable oral peptide delivery by overcoming gastrointestinal barriers

Citation: Cheng J, Wu P, Li C, et al. Sci Adv. 2026;12(3):eaea2989. PubMed

Study Design

• Preclinical mouse study, not a human trial
• Platform: self-immolative peptide prodrug conjugate (SIPPC) for inflammation-targeted oral delivery
• Built from a hydrophilic polyethylene glycol (PEG) segment, a reactive oxygen species (ROS)-responsive hydrophobic self-immolative module, and a hydrolyzable scaffold
• The conjugates self-assemble into micelle-like nanoparticles
• Tested with three anti-inflammatory peptides: KPV, Ac-QAW and IRW
• Mouse models: colitis and acute lung injury

Key Results

• The conjugates showed strong stability in the gut, efficient mucus penetration, and ROS-responsive release at inflamed sites
• In colitis mice, the KPV conjugate (proKPV) reached 3.8-fold greater colonic accumulation than free KPV
• proKPV showed enhanced efficacy even at a 20-fold lower dose
• Oral proKPV also accumulated in inflamed lungs and showed anti-inflammatory effects in mice with acute lung injury
• Ac-QAW and IRW conjugates showed comparable benefits

Relevance

The authors note that oral peptide drugs are held back by breakdown in the gut and poor intestinal absorption. This mouse study shows one engineering approach that delivered more KPV to inflamed tissue at a lower dose. It tested a specific prodrug conjugate, not plain KPV, and it reports no human data. Treat it as early delivery research, not evidence that oral KPV products work in people.

See Also

• Parent compound: KPV