Exploring a Ugi‐Mediated Polymerization‐Induced Self‐Assembly Approach to Peptoid Particles

This work investigates the synthesis of polypeptoid nanoparticles through Ugi-mediated polymerization-induced self-assembly (U-PISA), combining aqueous Ugi four-component polycondensation with PEG-based stabilization. Polypeptoid nano-objects were produced directly from amino acid-derived building blocks via a one-pot process under mild, open-air conditions. The effects of PEG molar mass and feed composition on particle formation and morphology were systematically examined, providing access to tunable spherical and worm-like nanostructures. The in situ formation of amphiphilic PEG-polypeptoid species suggests that nanoparticle formation proceeds through a PISA-like mechanism. However, the step-growth nature of the Ugi polycondensation implies that both PEG-functionalized and unconjugated polypeptoid chains may participate in nanoparticle assembly and stabilization. These results demonstrate that multicomponent polymerizations, such as Ugi polymerization, can be integrated into a PISA strategy, offering a simple route to polypeptoid nanoparticles with tunable morphologies and potential biomedical applications.