Abstract: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.
