Membrane-cross-linked polymersomes with tumor pH-tunable selective permeability as intelligent nanoreactors and drug delivery vehicles

Abstract Stimuli-responsive polymersomes have attracted great attention not only as smart drug delivery vehicles but also as intelligent artificial nanoreactors. Herein, we develop a series of membrane-cross-linked (MCL) polymersomes with cross-linking density-mediated and tumor pH-tunable selective membrane permeability for stimuli-responsive drug delivery and controllable enzymatic reaction. The diblock copolymers consisting of poly(ethylene glycol) (PEG) and copolymerized with methacrylate monomers containing piperidine or coumarin moieties were synthesized and self-assembled into polymersomes that can encapsulate both small molecule doxorubicin hydrochloride (DOX) and large molecule glucose oxidase (GOD). After photo-cross-linking, the optimized cross-linking density and pH-responsive segments endow the polymersomes with superior stability and ultra pH-sensitive selective membranes permeability upon changing pH from 7.4 to 6.5. Drug release and enzymatic reaction are triggered by pH change via the enhanced membrane permeability of the polymersomes loading DOX and GOD. With diffusion of small molecules into or out of the polymersomes including DOX, glucose, and O2, the massively generated hydrogen peroxide (H2O2) under the catalysis of GOD and the released DOX can synergistically kill cancer cells. Thus, the polymersomes with the tumor pH-responsive and cross-linking density-mediated membrane permeability show promising applications as a unique platform for cancer therapy.