Catalyst‐Free One‐Step Preparation of Self‐Crosslinked pH‐Responsive Vesicles

: The fabrication of block copolymer (BCP) vesicles with controlled membrane permeability and promising stability remains a considerable challenge. Herein, a new type of pH-responsive and self-crosslinked vesicle based on a hydrolytically hindered urea bond is reported. This kind of vesicle is formed by the self-assembly of a pH-responsive and hydrolytically self-crosslinkable copolymer poly(ethylene glycol)-block-poly[2-(3-(tert-butyl)-3-ethylureido)ethyl methacrylate-co-2-(diethylamino)ethyl methacrylate] (PEG-b-P(TBEU-co-DEA)). The BCP can be easily synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization of 2-(3-(tert-butyl)-3-ethylureido)ethyl methacrylate (TBEU) and 2-(diethylamino)ethyl methacrylate (DEA) using PEG-based macro-chain transfer agent. The copolymer could self-assemble into stable vesicles by the hydrophobic interaction and in situ cross-linking between amines and isocyanates after the hydrolysis of the hindered urea bonds without any catalyst. Dynamic light scattering (DLS) studies show that the vesicles exhibit enhanced stability against the dilution of organic solvent, and the size can be adjusted through the change of pH values. Moreover, the alkaline phosphatase-loaded vesicles can act as nano-reactor and enable free diffusion of small molecules into the vesicles, followed by the significantly improved fluorescence intensity of phosphate-caged fluorescein. This self-crosslinking and pH-sensitive vesicles may serve as a smart platform in controlled drug delivery and molecular reactor.