Degradable Diblock Copolymer Vesicles via Radical Ring-Opening Polymerization-Induced Self-Assembly in Aqueous Media

The development of degradable polymeric vesicles is essential for next-generation controlled delivery systems and responsive materials, particularly for therapy and diagnostics. However, achieving precise control over their synthesis and degradation behavior remains a significant challenge. Herein we report the synthesis of degradable diblock copolymer vesicles via radical ring-opening polymerization-induced self-assembly (rROPISA) in aqueous media. This approach employs radical ring-opening copolymerization (rROP) of a thionolactone with a water-miscible vinyl monomer to introduce cleavable thioester groups within the membrane-forming polymer chains. More specifically, a water-soluble poly(<i>N</i>,<i>N</i>-dimethylacrylamide) (PDMAC) precursor is chain-extended by statistically copolymerizing dibenzo[<i>c</i>,<i>e</i>]oxepane-5-thione (DOT) with 2-methoxyethyl acrylate (MEA) using a reversible addition-fragmentation chain transfer (RAFT) aqueous dispersion polymerization formulation. The disparity in reactivity between DOT and MEA is addressed using a comonomer-starved feed strategy, with MEA acting as a cosolvent for the water-insoluble DOT. This controlled feeding approach ensures a more uniform distribution of DOT repeat units within the hydrophobic core block, significantly improves copolymer composition control, enables DOT incorporation of up to ∼4 mol %, and enhances overall comonomer conversion. Compared to conventional one-shot batch syntheses, this strategy yielded vesicles with superior degradation profiles. Morphological characterization using cryogenic transmission electron microscopy (cryo-TEM), dynamic light scattering (DLS) and small-angle X-ray scattering (SAXS) confirmed the formation of well-defined vesicles. Hydrolytic degradation studies conducted in mildly basic aqueous media led to vesicle disintegration, as indicated by cryo-TEM, DLS, and SAXS analyses. Importantly, size exclusion chromatography (SEC) analysis revealed the formation of significantly shorter copolymer chains and final molecular weight distributions comparable to that of the nondegradable PDMAC precursor, indicating efficient hydrolytic degradation of the membrane-forming P(MEA-<i>stat</i>-DOT) block. This study provides valuable insights regarding the rational design of degradable vinyl-based diblock copolymer vesicles, which augurs well for potential biomedical applications.