摘要
Cartilage-targeting delivery of therapeutic agents is still an effective strategy for osteoarthritis(OA)therapy.Recently,scavenging for reactive oxygen species(ROS)and activating autophagy have been increasingly reported to treat OA effectively.In this study,we designed,for the first time,a dual-drug delivery system based on metal organic framework(MOF)-decorated mesoporous polydopamine(MPDA)which composed of rapamycin(Rap)loaded into the mesopores and bilirubin(Br)loaded onto the shell of MOF.The collagen II-targeting peptide(WYRGRL)was then conjugated on the surface of above nanocarrier to develop a cartilage-targeting dual-drug delivery nanoplatform(RB@MPMW).Our results indicated the sequential release of two agents from RB@MPMW could be achieved via near-infrared(NIR)laser irritation.Briefly,the rapid release of Br from the MOF shell exhibited excellent ROS scavenging ability and anti-apoptosis effects,however responsively reduced autophagy activity,to a certain extent.Meanwhile,following the NIR irradiation,Rap was rapidly released from MPDA core and further enhanced autophagy activation and chondrocyte protection.RB@MPMW continuously phosphorylated AMPK and further rescued mitochondrial energy metabolism of chondrocytes following IL-1βstimulation via activating SIRT1-PGC-1αsignaling pathway.Additionally,the cartilage-targeting property of peptide-modified nanocarrier could be monitored via Magnetic Resonance(MR)and IVIS imaging.More significantly,RB@MPMW effectively delayed cartilage degeneration in ACLT rat model.Overall,our findings indicated that the as-prepared dual-drug delivery nanoplatform exerted potent anti-inflammation and anti-apoptotic effects,rescued energy metabolism of chondrocytes in vitro and prevented cartilage degeneration in vivo,which thereby showed positive performance for OA therapy.
基金
supported by the National Natural Science Foundation of China(81871795,31771048 and 81702124)
Shanghai Municipal Health and Family Planning Commission(SHDC12017121)
Medical Engineering Cross Research Project of Shanghai Jiaotong University(YG2019QNB37)
Songjiang District Science and Technology Research project(18sjkjgg18).
