Self-Assembling Peptide Hydrogels for Mucosal Drug Delivery: Synthesis, Triggering Strategies, and Therapeutic Applications

Self-assembling peptide hydrogels (SAPHs) have emerged as promising platforms for mucosal drug delivery due to their excellent biocompatibility, programmable sequence design, and diverse triggering strategies. This review systematically discusses the molecular basis, synthesis techniques, and triggering strategies of SAPHs, highlighting how these elements collectively enable in situ gelation and on-demand drug release at mucosal sites. We also review applications across the oral, gastrointestinal, ocular, vaginal, middle ear, and respiratory mucosa, demonstrating the therapeutic potential of SAPHs in infection treatment, tissue repair, and immunomodulation. We further compare SAPHs with other mucosal delivery systems and summarize the clinical status of mucosal delivery products; although several products are in clinical use, no SAPH-based product has been approved for mucosal delivery, and the factors limiting clinical translation are discussed. Despite significant progress, several challenges remain, including balancing mechanical stability with degradation, ensuring batch-to-batch consistency, confirming long-term biosafety, and obtaining regulatory approval. With the integration of artificial intelligence-assisted design and modular programmable platforms, SAPHs hold considerable promise for precision mucosal drug delivery.