Oscillating the local milieu of polymersome interiors via single input-regulated bilayer crosslinking and permeability tuning

Guhuan Liu,Jie Cen,Shiyong Liu,Guoying Zhang,Jinming Hu,Jiajia Tan

doi:10.1038/s41467-022-28227-6

Guhuan Liu, Jie Cen + Show 4 more

Open Access

https://doi.org/10.1038/s41467-022-28227-6

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Abstract

The unique permselectivity of cellular membranes is of crucial importance to maintain intracellular homeostasis while adapting to microenvironmental changes. Although liposomes and polymersomes have been widely engineered to mimic microstructures and functions of cells, it still remains a considerable challenge to synergize the stability and permeability of artificial cells and to imitate local milieu fluctuations. Herein, we report concurrent crosslinking and permeabilizing of pH-responsive polymersomes containing Schiff base moieties within bilayer membranes via enzyme-catalyzed acid production. Notably, this synergistic crosslinking and permeabilizing strategy allows tuning of the mesh sizes of the crosslinked bilayers with subnanometer precision, showing discriminative permeability toward maltooligosaccharides with molecular sizes of ~1.4-2.6 nm. The permselectivity of bilayer membranes enables intravesicular pH oscillation, fueled by a single input of glucose. This intravesicular pH oscillation can further drive the dissipative self-assembly of pH-sensitive dipeptides. Moreover, the permeabilization of polymersomes can be regulated by intracellular pH gradient as well, enabling the controlled release of encapsulated payloads.

Highlights

The unique permselectivity of cellular membranes is of crucial importance to maintain intracellular homeostasis while adapting to microenvironmental changes
Glucose oxidase (GOx) and catalase (Cat) are loaded into pH-responsive polymersomes self-assembled from Schiff base-containing amphiphilic block copolymers (BCPs)
By varying the chemical structures, compositions, and hydrophobic block lengths, nanoassemblies with uniform morphologies including spherical micelles, vesicles, and large compound vesicles (LCVs) were obtained. These nanoassemblies were characterized by dynamic light scattering (DLS), transmission electron microscopy ((cryo)-TEM), and scanning electron microscopy (SEM) (Supplementary Figs. 7-9)

Summary

Introduction

The unique permselectivity of cellular membranes is of crucial importance to maintain intracellular homeostasis while adapting to microenvironmental changes. We report concurrent crosslinking and permeabilizing of pH-responsive polymersomes containing Schiff base moieties within bilayer membranes via enzyme-catalyzed acid production. Unlike liposomes assembled from phospholipids, polymersomes possess increased structural stability yet decreased membrane permeability, which is unfavorable for mimicking intracellular energy exchange and the selective transport of different substances. To this end, several approaches, such as the development of stimuli-responsive vescicles[25,26,27,28], post-modification of bilayer membranes[29,30,31], membrane protein insertion[32,33], have been applied to permeabilize polymersomes. The accumulation of GA results in local acidification within polymersome lumens until the depletion of glucose and the diffusion of phosphate ions to recover the pH, enabling local transient pH oscillations within polymersome interiors (Fig. 1)

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