Biomimetic nanodelivery of antagomiR-155-5p ameliorates wear particle-induced osteolysis by dual regulation of Gas6/Axl-mediated macrophage inflammation.

BACKGROUND: Aseptic loosening (AL) is the primary cause of prosthesis failure after total joint replacement, which is triggered by wear particle-induced macrophage activation, excessive inflammatory factor secretion and subsequent periprosthetic osteolysis. MicroRNAs (miRNAs) act as key regulators of this pathological cascade, yet the specific functional miRNAs and their precise regulatory mechanisms remain incompletely clarified. METHODS: mRNA-seq and miRNA-seq were performed in titanium particle (TiPs)-stimulated macrophages to screen osteolysis-associated miRNAs, with expression validation conducted in clinical periprosthetic osteolytic tissues. In vitro functional and mechanistic assays were used to verify the miR-155-5p/Gas6/Axl regulatory axis, and a mouse calvarial osteolysis model was applied for in vivo validation. Macrophage membrane-camouflaged PLGA-PEI nanoparticles loaded with antagomir-155-5p (Anta-155@MNPs) were constructed, and their local therapeutic efficacy was evaluated in murine osteolysis models. RESULTS: miR-155-5p was significantly upregulated in both TiPs-stimulated macrophages and clinical periprosthetic osteolytic tissues. Functionally, miR-155-5p promoted Stat1/p65 phosphorylation, proinflammatory cytokine production and M1 macrophage polarization by inhibiting the Gas6/Axl pathway via dual mechanisms: Mafb-mediated Gas6 transcriptional repression and Adam10-dependent Axl cleavage inhibition. In vivo, this axis exacerbated TiPs-induced calvarial osteolysis, while local Anta-155@MNPs administration markedly mitigated bone resorption and tissue inflammation. CONCLUSION: miR-155-5p drives TiPs-induced periprosthetic osteolysis via the Gas6/Axl signaling pathway, and targeted inhibition of miR-155-5p is a promising strategy to prevent artificial joint AL. THE TRANSLATIONAL POTENTIAL OF THIS ARTICLE: This study identifies the miR-155-5p/Gas6/Axl axis as a novel therapeutic target for AL, and the targeted Anta-155@MNPs delivery system provides a feasible preclinical strategy for clinical translation to treat wear particle-induced osteolysis.