Intelligent redox-responsive polymers, such as thioether-containing macromolecules, facilitate drug delivery and triggered release in biomedical applications. Moreover, reactive oxygen species (ROS)-responsive thioether systems based on poly(2-oxazoline)s (PAOx) platforms hold great promise for the development of highly biocompatible, stimuli-responsive biomaterials. However, thioether-containing PAOx are particularly difficult to synthesize because thioethers are incompatible with the cationic ring-opening polymerization (CROP). In this study, we aim at developing an alternative route to well-defined thioether-containing PAOx by a simple post-polymerization modification of linear polyethyleneimine. First, the synthesis of ROS-responsive PAOx homopolymers was optimized. Furthermore, ROS-sensitive amphiphilic diblock copolymers poly(ethylene glycol)-block-poly(2-methylthiomethyl-2-oxazoline) were synthesized by combining CROP with 2-oxazoline side-chain interchange via a polyethyleneimine block intermediate. In an aqueous environment, the copolymers self-assembled into thioether-containing micelles. These micelles were characterized by size exclusion chromatography, nuclear magnetic resonance, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, dynamic light scattering, differential scanning calorimetry, and transmission electron microscopy. In addition, treatment with diluted H₂O₂ destabilized the nanoparticles, thus demonstrating their oxidation-responsiveness. This approach provides key insights into the design and development of stimuli-responsive polymers for potential biomedical applications, such as drug delivery systems.