Bionic bearing-inspired lubricating microspheres with Immunomodulatory effects for osteoarthritis therapy
Xu He, Xingzhi Liu, Xinyi Cheng, Can Zhu, Yida Chen, Yi Wang, Yun Zhou, Hao Shen, Huilin Yang, Yong Xu, Qin Shi, Junjie Niu
Abstract
Inflammatory infiltration and inappropriate friction remain the two main challenges in treating osteoarthritis (OA). An effective treatment platform is anticipated to lubricate the cartilage and ameliorate intra-articular inflammation. Herein, injectable hydrogel microspheres with chondroitin sulfate (Chs)/sericin methacryloyl (SerMA) designed as the core and grafted with folic acid (FA)- and 78c-modified liposomes (78c@Lipo-FA) by DSPE-PEG2k-GPLGLAGQC (DPG) peptides, namely LFDCS, was formed by thin-film hydration and microfluidic methods. Physically, LFDCS exhibited cartilage lubrication and adhesion capability as the bionic bearings. Meanwhile, with the degradation of LFDCS, Chs were set out to promote chondrocyte function. Physiologically, 78c@Lipo-FA were released from LFDCS enzymatically responsible to matrix metalloprotein-9 (MMP9) due to the split of DPG motif, which specifically bound to classical-activated macrophages (M1) by ligating to FA receptor through FA and inhibit M1 function by 78c, consequently rescued cartilage from degradation by inflammation. Mechanically, an RNA sequencing analysis revealed that the LFDCS could ameliorate chondrocyte dysfunction by down-regulating PI3K/AKT signaling and inflammation response. LFDCS greatly reduced friction on articular surfaces, suppressed M1-induced inflammation and attenuated chondrocyte dysfunction in OA rats. In conclusion, the bionic bearing-inspired lubricating microspheres characterized by M1-phenotype macrophage-targeted addresses the unfavorable factors of both the physical and physiological microenvironments in macrophage-mediated diseases.