A Thioether-Functionalized Biomimetic Poly(2-oxazoline) Platform for Thermo-, Photo-, and Anion-Responsive Pseudopolypeptides

Poly(2-oxazoline)s (POxs) are versatile pseudopolypeptides, yet the incorporation of thioether side chains, a functional motif of methionine that can participate in oxidation, coordination, and stimuli-responsive transformations, remains underexplored. Here, we report the synthesis of a methionine-mimetic monomer, 2-(2-(methylmercapto)ethyl)-2-oxazoline (MMPOx), from 3-mercaptopropanoic acid and its optimized cationic ring-opening polymerization to form well-defined poly(2-(2-(methylmercapto)ethyl)-2-oxazoline) (PMMPOx). This pseudopolypeptide mimics polymethionine and shows UCST-type thermoresponsive phase behavior in organic-water mixed solvents. The presence of side-chain thioether groups enables postpolymerization modification with 2-nitrobenzyl bromide to generate a cationic polysulfonium architecture, P[MMPOx-NB][Br]. This cationization makes the P[MMPOx-NB][Br] water-soluble and introduces diverse functionalities, including photoresponsiveness, anion-responsiveness, and facile DNA polyplexation. Upon addition of anions (I –, ClO 4 –, and SCN – ), the aqueous solution of P[MMPOx-NB][Br] undergoes a transition from transparent to turbid and the turbid suspension reverts to transparent upon heating, demonstrating a reversible upper critical solution temperature (UCST)-type phase behavior. Photoirradiation triggers detachment of the photolabile nitrobenzyl group, converting the cationic P[MMPOx-NB][Br] into its water-insoluble neutral analogue, PMMPOx. This transformation enables phototriggered release of negatively charged ctDNA from the electrostatically bound P[MMPOx-NB][Br]/ctDNA polyplex, as evidenced by gel electrophoresis and photoluminescence analyses. Finally, DNA compaction by the cationic P[MMPOx-NB][Br] is investigated by measuring the Förster resonance energy transfer (FRET) efficiency between a FRET pair (FAM-TAMRA) labeled on a DNA. This work establishes a thioether-functionalized POx platform, showing its potential as a multifunctional, stimulus-responsive polymer for biomedical applications.