Stimuli-responsive self-assembly and structural transition of a glycosylated triblock terpolymer: construction of “Sweet” nanoparticles

Glycosylated nanoparticles were constructed from triblock terpolymers, and their well-defined morphology and responsiveness to pH and temperature were characterized using cryo-TEM and DLS. • Design and synthesis of a glycosylated triblock terpolymer via RAFT polymerization. • Stimuli-responsive self-assembly into glycosylated micelles and polyplex nanoparticles. • Polyplex micelles featuring a reversible “breathing” behavior driven by the shell dynamics. • Potential applications in drug delivery and biosensing through tunable nanostructures. Glycosylated nanoparticles, inspired by natural systems, hold great promise for biomedical applications such as targeted drug delivery and biosensing. However, achieving precise control over their self-assembly and responsiveness remains a challenge. In this study, we report the design, synthesis, and self-assembly behavior of a novel glycosylated triblock terpolymer with tunable stimulus responsiveness. The terpolymer with stimulus responsiveness was synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerization. The self-assembly of these triblock terpolymers into glycosylated micelles with distinct pH responsiveness was induced by increasing the temperature. Postpolymerization modification of the glycosylated triblock terpolymer enabled the synthesis of glycosylated polyplex micelles via complex condensation. Dynamic light scattering (DLS), transmission electron microscopy (TEM), and cryogenic transmission electron microscopy (cryo-TEM) revealed stimuli-induced structural transitions, including pH-dependent transformations from hierarchical nanoparticles and ‘bead-on-a-string’ assemblies to uniform spherical micelles. Additionally, the glycosylated polyplex micelles exhibited unique ‘breathing’ behavior, characterized by reversible size variations driven by structural adjustments in the stabilizing chains. These stimuli-responsive glycosylated nanoparticles mimic natural systems and present significant potential for biomedical applications such as targeted drug delivery and biosensing. This study lays a solid foundation for the development of advanced glycosylated nanostructures with tailored functionality and responsiveness.