In individuals afflicted with hemophilia,characterized by a deficiency of coagulation factor VIII(FVIII),the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arth...In individuals afflicted with hemophilia,characterized by a deficiency of coagulation factor VIII(FVIII),the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arthropathy(HA).Although clotting factor replacement therapy reduces joint bleeding clinically,clotting factors need to be injected frequently due to the rapid diffusion of the drug.Hence,a novel drug delivery approach may be developed to improve the drug therapy.Platelet-derived extracellular vesicles(PEVs)are known to possess anti-inflammatory and hemostatic properties and could be used as a potential HA therapy.In this study,we constructed a PEV-LS@FVIII nanotherapeutic system by combining thioketal(TK),liposomes(LS),and FVIII to form the LS@FVIII complexes,and then hybridizing PEV with LS@FVIII.Our results demonstrated that PEVLS@FVIII could efficiently facilitate FVIII delivery and specifically target the injured knee joint.Both in vitro and in vivo studies showed a reduction in the M1 phenotype of macrophages and an enhancement of the M2 phenotype,compared to FVIII free control.Furthermore,PEV-LS@FVIII appeared to alleviate HA-induced cartilage damage.In conclusion,our findings demonstrate that PEV-LS@FVIII could delay the progression of HA by targeting bleeding joints,modulating macrophage polarization to suppress inflammation,and mitigating cartilage damage.展开更多
基金supported by the Zhejiang Provincial Natural Science Foundation of China(LR23H270001 and LQ22H270006)National Natural Science Foundation of China(82274280 and 82305005).
文摘In individuals afflicted with hemophilia,characterized by a deficiency of coagulation factor VIII(FVIII),the occurrence of spontaneous recurrent intra-articular hemorrhage precipitates the emergence of hemophilic arthropathy(HA).Although clotting factor replacement therapy reduces joint bleeding clinically,clotting factors need to be injected frequently due to the rapid diffusion of the drug.Hence,a novel drug delivery approach may be developed to improve the drug therapy.Platelet-derived extracellular vesicles(PEVs)are known to possess anti-inflammatory and hemostatic properties and could be used as a potential HA therapy.In this study,we constructed a PEV-LS@FVIII nanotherapeutic system by combining thioketal(TK),liposomes(LS),and FVIII to form the LS@FVIII complexes,and then hybridizing PEV with LS@FVIII.Our results demonstrated that PEVLS@FVIII could efficiently facilitate FVIII delivery and specifically target the injured knee joint.Both in vitro and in vivo studies showed a reduction in the M1 phenotype of macrophages and an enhancement of the M2 phenotype,compared to FVIII free control.Furthermore,PEV-LS@FVIII appeared to alleviate HA-induced cartilage damage.In conclusion,our findings demonstrate that PEV-LS@FVIII could delay the progression of HA by targeting bleeding joints,modulating macrophage polarization to suppress inflammation,and mitigating cartilage damage.
