Fig. 1: Glucose-fueled self-catalyzed construction of transient acidic milieu within the aqueous lumen of enzyme-loaded polymersomes via self-regulated bilayer permeability.

a Polymersomes self-assembled from Schiff base-containing amphiphilic block copolymers were loaded with glucose oxidase (GOx) and catalase (Cat). Externally added glucose diffuses across initially hydrophobic vesicle bilayers into the aqueous lumen and GOx/Cat-mediated cascade enzymatic reactions generate gluconic acid (GA), which partially ionizes and leads to lumen pH decrease. The local acidic milieu triggers the hydrolysis of side chain Schiff base moieties within bilayers, leading to subsequent self-immolative degradation, primary amine generation and bilayer crosslinking, and concurrent hydrophobic-to-hydrophilic transition. This process is accompanied by the elevation of glucose permeability through bilayers and enhanced GOx activity due to local acidic lumen. These concurrent events facilitate the construction of a closed positive feedback cycle in a self-catalyzed manner toward enzymatic reaction rates and lumen pH decrease, which further accelerates Schiff base hydrolysis and enhances bilayer permeability. At later stages, external buffer ions and partially ionized GA in the aqueous lumen start to diffuse across newly generated hydrophilic crosslinked bilayers, leading to lumen pH increase and GOx activity decrease. Upon feeding with glucose fuel, we construct transient acidic milieu in the aqueous lumen of vesicles by coordinating cascade enzymatic reactions with bilayer permeability. By finely tuning the extent of bilayer crosslinking and corresponding mesh sizes, pH oscillation in the aqueous lumen could be established via the addition of multiple glucose dosages. b Chemical structures of amphiphilic block copolymers, BPN and BPF, and mechanisms of acidic pH-triggered Schiff base hydrolysis, self-immolative cleavage, amidation-mediated bilayer crosslinking, and regulated vesicle bilayer permeabilization.