Supramolecular Enzyme-Peptide Gels for Localized Therapeutic Biocatalysis

Enzyme therapeutics are often compromised by poor accumulation within target tissues, necessitating high doses that can exacerbate off-target effects. We report an injectable supramolecular enzyme-peptide gel platform for prolonged local enzyme retention in vivo. The gel is based on CATCH(+/-) (Co-Assembling Tags based on CHarge-complementarity), cationic and anionic peptide pairs that form β-sheet fibrils upon mixing. Enzymes recombinantly fused to CATCH(-) peptide integrate into CATCH(+/-) β-sheet fibrils during assembly, resulting in an enzyme-peptide gel. Catalytically-active gels were fabricated with four disparate enzymes: CATCH(-)-NanoLuc luciferase, CATCH(-)-cutinase, CATCH(-)-uricase, and CATCH(-)-adenosine synthase A. CATCH(-)-cutinase gels demonstrated tunability of the platform, while CATCH(-)-NanoLuc gels demonstrated prolonged tissue retention relative to soluble enzyme. CATCH(-)-uricase gels resolved localized inflammation in a gout model, while CATCH(-)-adenosine synthase A gels suppressed localized lipopolysaccharide-induced inflammation. Modular and tunable enzyme content, coupled with prolonged tissue retention, establish CATCH enzyme-peptide gels as a generalizable vehicle for effective local therapeutic biocatalysis.