Supramolecular Enzyme-Peptide Gels for Localized Therapeutic Biocatalysis

Enzyme therapeutics are often compromised by poor accumulation within target tissues, necessitating repeated systemic dosing that can exacerbate side-effects like immunogenicity. We report an injectable supramolecular enzyme-peptide gel platform for prolonged local enzyme retention in vivo. The gel is based on CATCH(+/-) ( C o- A ssembling T ags based on CH arge-complementarity), cationic and anionic peptide pairs that form β-sheet fibrillar gels upon mixing. Five disparate enzymes recombinantly fused to CATCH(-) peptide integrate into CATCH(+/-) fibrils during assembly, resulting in five single-enzyme and three dual-enzyme catalytically-active enzyme-peptide gels. CATCH gels enable titratable catalytic activity and prolonged localized retention. Gels of uricase, an FDA-approved but systemically-ineffective enzyme therapy for gout, rapidly dissolve gout crystals, with low risk of anaphylaxis after repeat dosing. Dual-enzyme gels of uricase and anti-inflammatory indoleamine 2,3-dioxygenase outperformed either single-enzyme formulation by concomitantly dissolving the crystals and suppressing pro-inflammatory neutrophil functions. Modular and tunable enzyme content, coupled with prolonged retention, establish CATCH enzyme-peptide gels as a generalizable vehicle for effective local therapeutic biocatalysis.