| Summary: | Reactive oxygen species (ROS) are essential signaling molecules that maintain intracellular redox balance; however, the overproduction of ROS often causes dysfunction in redox homeostasis and induces serious diseases. Antioxidants are crucial candidates for reducing overproduced ROS; however, most antioxidants are less effective than anticipated. Therefore, we designed new polymer-based antioxidants based on the natural amino acid, cysteine (Cys). Amphiphilic block copolymers, composed of a hydrophilic poly(ethylene glycol) (PEG) segment and a hydrophobic poly(cysteine) (PCys) segment, were synthesized. In the PCys segment, the free thiol groups in the side chain were protected by thioester moiety. The obtained block copolymers formed self-assembling nanoparticles (Nano<sup>Cys(Bu)</sup>) in water, and the hydrodynamic diameter was 40–160 nm, as determined by dynamic light scattering (DLS) measurements. Nano<sup>Cys(Bu)</sup> was stable from pH 2 to 8 under aqueous conditions, as confirmed by the hydrodynamic diameter of Nano<sup>Cys(Bu)</sup>. Finally, Nano<sup>Cys(Bu)</sup> was applied to sepsis treatment to investigate the potential of Nano<sup>Cys(Bu)</sup>. Nano<sup>Cys(Bu)</sup> was supplied to BALB/cA mice by free drinking for two days, and lipopolysaccharide (LPS) was intraperitoneally injected into the mice to prepare a sepsis shock model (LPS = 5 mg per kg body weight (BW)). Compared with the Cys and no-treatment groups, Nano<sup>Cys(Bu)</sup> prolonged the half-life by five to six hours. Nano<sup>Cys(Bu)</sup>, designed in this study, shows promise as a candidate for enhancing antioxidative efficacy and mitigating the adverse effect of cysteine.
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