Chiral D-peptide supramolecular hydrogel for minimizing postoperative pancreatic fistula by devitalizing pancreatic enzymes

Postoperative pancreatic fistula (POPF), is regarded as one of the most challenging complications following pancreatic and intestinal surgeries, posing significant risks to patients due to rapid tissue degradation caused by enzymes such as proteases and lipases released from the pancreas. The incorporation of D-enantiomerism into the backbone-side-chain connectivity and geometry of peptides offers a promising solution to enhance their resistance against proteases and lipases substantially. Therefore, this study successfully developed a chiral D-peptide supramolecular hydrogel known as CDPSH within a supramolecular hydrogel called LPSH. LPSH is composed of two peptides capable of self-assembling into intricate nanofibers that interweave into a mesh-like structure, facilitated by the presence of Ca²⁺ ions and blood coagulation factor FXIIIa. Remarkably, the hydrogel properties and mechanical characteristics of LPSH remained intact when incorporating D-enantiomerism, leading to the emergence of CDPSH. CDPSH exhibited a novel functionality by effectively inhibiting the enzymatic activities of trypsin, chymotrypsin, and lipase. Functioning as a self-healing physical barrier with resistance against proteolysis, CDPSH successfully encapsulated pancreatic fluid in rats with POPF. Furthermore, it significantly mitigated the inflammation caused by POPF while maintaining an excellent biosafety profile. In conclusion, the use of D-enantiomeric peptides in constructing supramolecular hydrogels not only provides a novel approach for creating biocompatible, biomimetic, and injectable hydrogels through peptide self-assembly but also introduces an innovative strategy for developing highly stable and multifunctional hydrogels with clinical applications.