title: Engineering Intracellular Delivery Nanocarriers and Nanoreactors from Oxidation-Responsive Polymersomes via Synchronized Bilayer Cross-Linking and Permeabilizing Inside Live Cells.
abstract: Reactive oxygen species (ROS) and oxidative stress are implicated in various physiological and pathological processes, and this feature provides a vital biochemical basis for designing novel therapeutic and diagnostic nanomedicines. Among them, oxidation-responsive micelles and vesicles (polymersomes) of amphiphilic block copolymers have been extensively explored; however, in previous works, oxidation by ROS including H2O2 exclusively leads to microstructural destruction of polymeric assemblies. For oxidation-responsive polymersomes, fast release of encapsulated hydrophilic drugs and bioactive macromolecules will occur upon microstructural disintegration. Under certain application circumstances, this does not meet design requirements for sustained-release drug nanocarriers and long-acting in vivo nanoreactors. Also note that conventional polymersomes possess thick hydrophobic bilayers and compromised membrane permeability, rendering them as ineffective nanocarriers and nanoreactors. We herein report the fabrication of oxidation-responsive multifunctional polymersomes exhibiting intracellular milieu-triggered vesicle bilayer cross-linking, permeability switching, and enhanced imaging/drug release features. Mitochondria-targeted H2O2 reactive polymersomes were obtained through the self-assembly of amphiphilic block copolymers containing arylboronate ester-capped self-immolative side linkages in the hydrophobic block, followed by surface functionalization with targeting peptides. Upon cellular uptake, intracellular H2O2 triggers cascade decaging reactions and generates primary amine moieties; prominent amidation reaction then occurs within hydrophobic bilayer membranes, resulting in concurrent cross-linking and hydrophobic-to-hydrophilic transition of polymersome bilayers inside live cells. This process was further utilized to achieve integrated functions such as sustained drug release, (combination) chemotherapy monitored by fluorescence and magnetic resonance (MR) imaging turn-on, and to construct intracellular fluorogenic nanoreactors for cytosolic thiol-containing bioactive molecules.
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Zhengyu
authors.initials: Z
authors.lastname: Deng
authors.affiliation: Department of Radiology, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui 230022, China.
authors.forename: Yinfeng
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Department of Radiology, The First Affiliated Hospital of Anhui Medical University , Hefei, Anhui 230022, China.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Yu
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Guhuan
authors.initials: G
authors.lastname: Liu
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Hu
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhang
authors.affiliation: CAS Key Laboratory of Soft Matter Chemistry, Hefei National Laboratory for Physical Sciences at the Microscale, iChEM (Collaborative Innovation Center of Chemistry for Energy Materials), Department of Polymer Science and Engineering, University of Science and Technology of China , Hefei, Anhui 230026, China.
authors.forename: Shiyong
authors.initials: S
authors.lastname: Liu
mesh_terms: D004337:Drug Carriers / Q000737:chemistry*; D065546:Drug Liberation; D006367:HeLa Cells; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D057927:Hydrophobic and Hydrophilic Interactions; D042541:Intracellular Space / Q000378:metabolism*; D036103:Nanotechnology; D010084:Oxidation-Reduction; D010539:Permeability; D011108:Polymers / Q000737:chemistry*; D013438:Sulfhydryl Compounds / Q000737:chemistry
chemical_list: D004337:Drug Carriers; D011108:Polymers; D013438:Sulfhydryl Compounds; D006861:Hydrogen Peroxide