Background <p>Aseptic prosthesis loosening caused by wear particles is a major complication in patients with osteoarthritis following total joint replacement. Despite advancements in treatment, the underlying mechanisms remain poorly understood, and effective therapies are still lacking.</p> Methods <p>In this study, we investigated the effects of titanium particles on osteoclast and osteoblast differentiation through both in vitro and in vivo experiments.</p> Results <p>Our findings revealed that titanium particles not only promote the differentiation of RAW264.7 cells into osteoclasts and enhance the secretion of inflammatory factors but also inhibit the differentiation of BMSCs into osteoblasts and reduce the expression of Wnt signaling pathway-related factors. Furthermore, using a mouse model of knee prosthesis loosening and AAV-mediated gene therapy, we demonstrated that the combination of <i>TNF-α</i> interference and <i>Wnt3a</i> overexpression was more effective than single-gene therapy in reducing inflammatory cell infiltration, promoting bone formation, and mitigating bone destruction.</p> Conclusions <p>These results highlight the dual role of titanium particles in periprosthetic osteolysis and underscore the potential of a gene therapy strategy targeting both inflammatory factors and the Wnt signaling pathway to improve knee prosthesis loosening. This study provides a scientific foundation for developing novel therapeutic approaches.</p>