Osteoarthritis(OA)is the most common disabling joint disease with no effective disease modifying drugs.Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and amel...Osteoarthritis(OA)is the most common disabling joint disease with no effective disease modifying drugs.Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models,representing a novel therapeutic strategy.In this study,we demonstrated that extracellular vesicles derived from human umbilical cord mesenchymal stem cells(hUC-EVs)could maintain chondrocyte homeostasis and alleviate OA,and further revealed a novel molecular mechanism of this therapeutic effect.miR-223,which could directly bind with the 3′UTR of NLRP3 mRNA,was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting.For enhancing the effect on mitigating osteoarthritis,exogenous miR-223 was loaded into hUC-EVs by electroporation,and a collagen II-targeting peptide(WYRGRL)was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage.The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis,and offered excellent results for the treatment of OA.This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered extracellular vesicles in OA treatment.展开更多
基金the Key Project of National Natural Science Foundation of China(81830076)the National Natural Science Foundation of China(82272568)+1 种基金the Shanghai Engineering Technology Research Center and Professional Technology Service Platform project of 2020“Science and Technology Innovation Action Plan”of Shanghai(20DZ2254100)the Biomedical Technology Support Special Project of Shanghai 2021“Science and Technology Innovation Action Plan”(21S31902300).
文摘Osteoarthritis(OA)is the most common disabling joint disease with no effective disease modifying drugs.Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models,representing a novel therapeutic strategy.In this study,we demonstrated that extracellular vesicles derived from human umbilical cord mesenchymal stem cells(hUC-EVs)could maintain chondrocyte homeostasis and alleviate OA,and further revealed a novel molecular mechanism of this therapeutic effect.miR-223,which could directly bind with the 3′UTR of NLRP3 mRNA,was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting.For enhancing the effect on mitigating osteoarthritis,exogenous miR-223 was loaded into hUC-EVs by electroporation,and a collagen II-targeting peptide(WYRGRL)was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage.The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis,and offered excellent results for the treatment of OA.This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered extracellular vesicles in OA treatment.
