Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis:Toward a precision therapy

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.

Cartilage-targeting and inflammatory-responsive nanocarriers for effective osteoarthritis treatment via reactive oxygen species scavenging and anti-angiogenesis

Osteoarthritis(OA),a common disabling joint disease,is highly associated with microenvironmental changes in the cartilage and subchondral bone.Elevated reactive oxygen species(ROS)in the cartilage and subchondral bone angiogenesis accelerate articular cartilage erosion.New cartilage-targeting drug deliv-ery systems that are aimed at preventing ROS production and angiogenesis may be of clinical significance for OA treatment.Herein,an ROS scavenger and an inflammatory-responsive nanocarrier are designed by immobilizing the natural polyphenol(curcumin)in chitosan-catechol nanoformulations(Cur-CS-C NPs)via boronate ester.The robust cartilage-targeting effects and ROS scavenging capacities of Cur-CS-C NPs were respectively determined in cartilage explants and chondrocytes.Intra-articular injection of Cur-CS-C NPs in OA rat models efficiently suppressed angiogenesis and cartilage degradation partially via the ROS-mediated NF-κB/PI3K-Akt signaling pathway.The developed curcumin-functionalized nanocarriers can significantly delay OA progression and provide a promising therapeutic strategy for other inflamma-tory diseases that are characterized by oxidative stress and angiogenesis.