Polypeptide Single‐Chain Nanoparticle Derived Artificial Enzyme

Polyamino acids synthesized via ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) monomers offer a scalable route to functional polypeptides, but the lack of sequence specificity limits their ability to fold and function like natural enzymes. Here, a series of artificial enzymes is developed based on single-chain nanoparticles (SCNPs) formed through intramolecular folding of a triblock copolypeptide, polyethylene glycol-b-poly(L-glutamic acid)-b-poly(oligo(ethylene glycol)-L-glutamate) (PEG₁₁₃-b-PGlu₁₁₂-b-P(Glu-EG₂)₉₉). The central poly-Glu block is intramolecularly cross-linked via coordination with transition metal ions (Fe²⁺/Fe³⁺, Mn²⁺, Co²⁺, Cu²⁺/Zn²⁺), mimicking the natural folding of polypeptides into proteins. Co-precipitation with ammonia water generates metal/alloy oxide nanoclusters within the cross-linked polyGlu domain, providing a large surface-to-volume ratio. The metal oxide nanoclusters function as coenzymes. They not only facilitate a structural transition from α-helices to β-strands within the cross-linked polyGlu domain but also demonstrate specific peroxidase (POD) or superoxide dismutase (SOD) activities, which are tailored to the specific metal species involved. The FeOx-complexed artificial enzyme (Fe-enzyme) is selected to exemplify its therapeutic effects of mitigating oxidative stress and inflammation in a rheumatoid arthritis mouse model. These artificial enzymes feature a soft, degradable polypeptide skeleton, tunable side-chain functionalities, high enzyme-like activity with minimal metal content (< 5 wt.%), and secondary structures similar to natural proteins.