Role of miR-21-5p in the protective effects of PLGA-encapsulated extracellular vesicles from urine-derived stem cells on periprosthetic osteolysis

Abstract

Periprosthetic osteolysis (PPOL), a form of aseptic osteolysis, accounts for most total hip arthroplasty (THA) revisions, necessitating the development of effective therapeutic strategies. We aimed to investigate the anti-inflammatory effects of poly(lactic-co-glycolic acid) (PLGA) nanoparticles-encapsulated extracellular vesicles (EVs) obtained from human urine-derived stem cells (USC-EVs) on osteolysis and elucidate the underlying mechanism. PLGA nanoparticles-encapsulated USC-EVs (PLGA-EVs) were synthesized by mechanical double-emulsion method. We locally injected PLGA-EVs into a mouse calvarial osteolysis model and evaluated their efficacy using micro-computed tomography and histological analyses. We assessed the osteoclastogenesis of RAW264.7 cells co-cultured with USC-EVs and determined the expression levels of inflammatory genes using qRT-PCR. Based on the microarray data and qRT-PCR results, we focused on microRNA-21–5p (miR-21–5p), a known regulator of the inflammatory response. We used specific miRNA antagomirs to examine miR-21–5p's role in the USC-EV-mediated inflammation regulation and osteolysis inhibition. Additionally, miR-21–5p's effect on PTEN was also analyzed. USC-EVs were efficiently endocytosed by RAW264.7 cells in vitro, decreasing osteoclastogenesis and reducing the expression of inflammatory genes. Locally injected USC-EVs persisted for ∼2 weeks and significantly mitigated osteolysis in vivo. Moreover, PLGA-EVs cloud be internalized by RAW264.7 cells in vitro and locally sustain a higher concentration in vivo. MiR-21–5p was highly enriched in USC-EVs and mediated the anti-inflammatory effects of USC-EVs by inhibiting PTEN. PLGA-encapsulated USC-EVs alleviated aseptic osteolysis partly through miR-21–5p-mediated anti-inflammatory actions, highlighting their potential as therapeutic agents for PPOL.