Development of a Novel Ultra‐Acidic Self‐Assembling Peptides‐Based Hydrogel System for pH‐Tunable Nanobody Delivery

Abstract Self‐assembling peptide hydrogels are promising scaffolds for drug delivery, however, the costly chemical synthesis of peptides has limited their widespread application. This study develops an innovative biological recombinant strategy for (RADA)₅ peptide production by fusing with a fibronectin fragment in Escherichia coli. Notably, it is reported for the first time, (RADA)₅ peptides gelates at an extremely acidic pH of 1.2, indicating potential application in the gastrointestinal tract. Circular dichroism reveals a characteristic β‐sheet structure and transmission electron microscopy exhibits a dense and interwoven nanofiber network. The (RADA)₅ peptide hydrogels demonstrate a pH‐responsive release with a substantial nanobody release at pH 6.8 (≈80%) and minimal release at pH 2.0 (<30%). This behavior allows fine‐tuning of nanobody release, potentially enabling retention in the acidic stomach and targeted release in the intestines. Within 24 h, <18% of the encapsulated nanobodies are released at pH 2.0, with sustained release observed upon transition to pH 6.8, achieving a cumulative release of 55% over 14 days. In conclusion, the novel ultra‐acidic (RADA)₅ peptide hydrogels are promising for sustained and controlled release of nanobodies in gastrointestinal disease treatment.