title: PEGylated graphene oxide elicits strong immunological responses despite surface passivation.
abstract: Engineered nanomaterials promise to transform medicine at the bio-nano interface. However, it is important to elucidate how synthetic nanomaterials interact with critical biological systems before such products can be safely utilized in humans. Past evidence suggests that polyethylene glycol-functionalized (PEGylated) nanomaterials are largely biocompatible and elicit less dramatic immune responses than their pristine counterparts. We here report results that contradict these findings. We find that PEGylated graphene oxide nanosheets (nGO-PEGs) stimulate potent cytokine responses in peritoneal macrophages, despite not being internalized. Atomistic molecular dynamics simulations support a mechanism by which nGO-PEGs preferentially adsorb onto and/or partially insert into cell membranes, thereby amplifying interactions with stimulatory surface receptors. Further experiments demonstrate that nGO-PEG indeed provokes cytokine secretion by enhancing integrin β8-related signalling pathways. The present results inform that surface passivation does not always prevent immunological reactions to 2D nanomaterials but also suggest applications for PEGylated nanomaterials wherein immune stimulation is desired.
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.|University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Nana
authors.initials: N
authors.lastname: Luo
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Weber
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.|University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Wang
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA.
authors.forename: Binquan
authors.initials: B
authors.lastname: Luan
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Hua
authors.initials: H
authors.lastname: Yue
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.|University of Chinese Academy of Sciences, Beijing 100049, PR China.
authors.forename: Xiaobo
authors.initials: X
authors.lastname: Xi
authors.affiliation: Institute of Biomechanics and Medical Engineering, Department of Engineering Mechanics, Tsinghua University, Beijing 100084, PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Du
authors.affiliation: Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, PR China.
authors.forename: Zaixing
authors.identifier: 0000-0003-3521-6867
authors.initials: Z
authors.lastname: Yang
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Computational Biology Center, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA.|Institute of Quantitative Biology and Medicine, SRMP and RAD-X, Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, PR China.|Department of Chemistry, Columbia University, New York, New York 10027, USA.
authors.forename: Ruhong
authors.identifier: 0000-0001-8624-5591
authors.initials: R
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Biochemical Engineering, Institute of Process Engineering, Chinese Academy of Sciences, Beijing 100190, PR China.|University of Chinese Academy of Sciences, Beijing 100049, PR China.|Jiangsu National Synergetic Innovation Center for Advanced Materials (SICAM), Nanjing Tech University, Nanjing 211816, PR China.
authors.forename: Guanghui
authors.initials: G
authors.lastname: Ma
mesh_terms: D000327:Adsorption; D000818:Animals; D001698:Biomedical Engineering / Q000379:methods; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D020099:Coated Materials, Biocompatible / Q000737:chemistry / Q000494:pharmacology*; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006108:Graphite / Q000737:chemistry / Q000494:pharmacology*; D007109:Immunity / Q000187:drug effects*; D039641:Integrin beta Chains / Q000276:immunology / Q000378:metabolism; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D056004:Molecular Dynamics Simulation; D049329:Nanostructures / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry / Q000494:pharmacology*; D061251:Primary Cell Culture; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013499:Surface Properties
chemical_list: D020099:Coated Materials, Biocompatible; D016207:Cytokines; D039641:Integrin beta Chains; C000628730:graphene oxide; C094865:integrin beta8; D011092:Polyethylene Glycols; D006108:Graphite