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

Oral delivery of peptide therapeutics remains challenging due to gastrointestinal (GI) degradation and poor intestinal absorption. Here, we propose a self-immolative peptide prodrug conjugate (SIPPC) platform for inflammation-targeted oral delivery, integrating a hydrophilic polyethylene glycol segment, a reactive oxygen species (ROS)-responsive hydrophobic self-immolative module, and a hydrolyzable scaffold, which collectively enable spontaneous assembly into micelle-like nanoparticles. Using three anti-inflammatory peptides (KPV, Ac-QAW, and IRW), we demonstrated that the engineered conjugates exhibit remarkable GI stability, efficient mucus penetration, and ROS-responsive release at inflamed sites. In colitis mice, the KPV-based conjugate (proKPV) achieved a 3.8-fold greater colonic accumulation than free KPV, with enhanced efficacy even at a 20-fold lower dose. Beyond therapeutic effects in the colitis model, oral proKPV substantially accumulated in inflamed lungs and exhibited potent anti-inflammatory efficacy in mice with acute lung injury. Ac-QAW and IRW-based conjugates exhibited comparable benefits, underscoring SIPPC as a transformative paradigm for oral peptide therapeutics, offering substantial promise for clinical translation in inflammatory disorders.