Self-assembly of PEG-b-PDLLA and PEG-b-PLGA nano-sized polymersomes through chain mobility and kinetic control

While polymersomes hold great promise as innovative drug delivery systems, their formulation is often hindered by the inherent complexity of self-assembly, where the competition between thermodynamically favored structures and kinetically trapped non-equilibrium states makes it particularly challenging to obtain homogeneous vesicle populations. We here report a robust and reproducible formulation method for the preparation of biodegradable polymersomes from PEG-b-PDLLA and PEG-b-PLGA block copolymers. By systematically varying solvent quality, water content and temperature, we demonstrate a sphere-to-worm-to-vesicle transition and how chain mobility and kinetic barriers dictate the self-assembly pathway from micelles to vesicles. We thus establish a simple formulation strategy by finely balancing solvent quality and temperature to produce monodisperse, nano-sized and dynamically stable polymersomes with tunable membrane thickness. The incorporation of glycolide units further provides control over hydrolytic degradation while preserving the vesicle formation. Overall, this study establishes a rational framework for designing biodegradable polymersomes with predictable structural properties, reinforcing their potential for advanced nanomedicine applications.