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bioRxiv · 10.1101/2024.09.06.611628

Supramolecular Enzyme-Peptide Gels for Localized Therapeutic Biocatalysis

Fuchs, M.·Seroski, D. T.·Soto Morales, B.·Melgar, L.·Scibilio, G.·Ziegler, A.·Liu, R.·Keselowsky, B. G.·Hudalla, G. A.
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Abstract

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(+/-) (Co-Assembling Tags based on CHarge-complementarity), cationic and anionic peptide pairs that form {beta}-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.

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Fuchs, M., Seroski, D. T., Soto Morales, B., Melgar, L., Scibilio, G., Ziegler, A., Liu, R., Keselowsky, B. G., Hudalla, G. A.. 2024-09-08. Supramolecular Enzyme-Peptide Gels for Localized Therapeutic Biocatalysis. https://doi.org/10.1101/2024.09.06.611628

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