This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation,in which neutrophil extracellular vesicles(NEVs)are coated onto reactive oxygen...This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation,in which neutrophil extracellular vesicles(NEVs)are coated onto reactive oxygen species(ROS)-sensitive probucol-based polyprodrug nanoparticles(NPPBNPs).This NEV-camouflaged biomimetic nanoformulation holds significant potential for the effective treatment of cerebral ischemia-reperfusion injury(CIRI),offering multifaceted therapeutic effects,such as ROS elimination,inhibition of oxidative stress-induced neuronal apoptosis,attenuation of glial hyperactivation,and suppression of pro-inflammatory mediator secretion.In a murine CIRI model,NPPBNPs markedly enhanced neuronal viability,ameliorated the ischemic penumbra,restored behavioral functions,and exhibited an acceptable safety profile.The therapeutic mechanism of NPPBNPs involves NEV-mediated camouflage,which enables selective targeting of the pathological endothelium,thereby reducing peripheral neutrophil recruitment and facilitating blood-brain barrier(BBB)transport.Upon internalization by neurons,astrocytes,and microglia within ischemic regions,NPPBNPs respond to elevated intracellular ROS levels by releasing probucol in a controlled manner,which synergistically mitigates oxidative stress and inflammatory responses in CIRI-affected areas.Collectively,this multifunctional biomimetic nanoformulation represents a promising and practical strategy for the safe and effective treatment of CIRI.展开更多
A wide array of chemokine receptors,including CCR2,are known to control Treg migration.Here,we report that CCR2 regulates Tregs beyond chemotaxis.We found that CCR2 deficiency reduced CD25 expression by FoxP3^(+) Treg...A wide array of chemokine receptors,including CCR2,are known to control Treg migration.Here,we report that CCR2 regulates Tregs beyond chemotaxis.We found that CCR2 deficiency reduced CD25 expression by FoxP3^(+) Treg cells.Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type(WT)and CCR2−/−strains.Thus,CCR2 deficiency resulted in profound loss of CD25 ^(hi) FoxP3^(+) Tregs in secondary lymphoid organs as well as in peripheral tissues.CCR2−/−Treg cells were also functionally inferior to WT cells.Interestingly,these changes to Treg cells did not depend on CCR2+monocytes/moDCs(the cells where CCR2 receptors are most abundant).Rather,we demonstrated that CCR2 was required for TLR-stimulated,but not TCR-or IL-2-stimulated,CD25 upregulation on Treg cells.Thus,we propose that CCR2 signaling can increase the fitness of FoxP3^(+) Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.展开更多
基金supported by the National Natural Science Foundation of China(32201150,82271321,12032007,and 32471366)the Natural Science Foundation of Chongqing(CSTB2022NSCQ-MSX0096 and CSTB2023NSCQ-LZX0033)+2 种基金the Science and Technology Innovation Project of Jinfeng Laboratory,Chongqing,China(jfkyjf202203001)the Fundamental Research Funds for the Central Universities(2024CDJCGJ-016,2023CDJYGRH-ZD03)the Shenzhen Science and Technology Program(JCYJ20230807111011024).
文摘This study leverages the unique advantages of polyprodrug systems and biomimetic technology to develop a novel biomimetic nanoformulation,in which neutrophil extracellular vesicles(NEVs)are coated onto reactive oxygen species(ROS)-sensitive probucol-based polyprodrug nanoparticles(NPPBNPs).This NEV-camouflaged biomimetic nanoformulation holds significant potential for the effective treatment of cerebral ischemia-reperfusion injury(CIRI),offering multifaceted therapeutic effects,such as ROS elimination,inhibition of oxidative stress-induced neuronal apoptosis,attenuation of glial hyperactivation,and suppression of pro-inflammatory mediator secretion.In a murine CIRI model,NPPBNPs markedly enhanced neuronal viability,ameliorated the ischemic penumbra,restored behavioral functions,and exhibited an acceptable safety profile.The therapeutic mechanism of NPPBNPs involves NEV-mediated camouflage,which enables selective targeting of the pathological endothelium,thereby reducing peripheral neutrophil recruitment and facilitating blood-brain barrier(BBB)transport.Upon internalization by neurons,astrocytes,and microglia within ischemic regions,NPPBNPs respond to elevated intracellular ROS levels by releasing probucol in a controlled manner,which synergistically mitigates oxidative stress and inflammatory responses in CIRI-affected areas.Collectively,this multifunctional biomimetic nanoformulation represents a promising and practical strategy for the safe and effective treatment of CIRI.
基金We thank M.Dayton,Li Sun,and Lisa Reid for technical assistanceThis work was supported by the Rebecca L.Cooper Foundation,National Health and Medical Research Council of Australia(NHMRC)grants(1037321,1080321,1105209,1143976)+1 种基金an NHMRC Independent Research Institutes Infrastructure Support Scheme grant(361646)a Victorian State Government Operational Infrastructure Support grant.
文摘A wide array of chemokine receptors,including CCR2,are known to control Treg migration.Here,we report that CCR2 regulates Tregs beyond chemotaxis.We found that CCR2 deficiency reduced CD25 expression by FoxP3^(+) Treg cells.Such a change was also consistently present in irradiation chimeras reconstituted with mixed bone marrow from wild-type(WT)and CCR2−/−strains.Thus,CCR2 deficiency resulted in profound loss of CD25 ^(hi) FoxP3^(+) Tregs in secondary lymphoid organs as well as in peripheral tissues.CCR2−/−Treg cells were also functionally inferior to WT cells.Interestingly,these changes to Treg cells did not depend on CCR2+monocytes/moDCs(the cells where CCR2 receptors are most abundant).Rather,we demonstrated that CCR2 was required for TLR-stimulated,but not TCR-or IL-2-stimulated,CD25 upregulation on Treg cells.Thus,we propose that CCR2 signaling can increase the fitness of FoxP3^(+) Treg cells and provide negative feedback to counter the proinflammatory effects of CCR2 on myeloid cells.
