Fused exosomal targeted therapy in periprosthetic osteolysis through regulation of bone metabolic homeostasis

The onset of periprosthetic osteolysis is mediated by wear particles following artificial arthroplasty. This manifests as a disturbed bone metabolism microenvironment, characterized by insufficient osteogenesis and angiogenesis, and enhanced osteoclastic activity. To target and remodel the homeostatic environment of bone metabolism in the sterile region around the prosthesis, we successfully pioneered the proposal and construction of a fused exosome (f-exo) system with M2 macrophage-derived exosomes (M2-exo) and urine-derived stem cell exosomes (USC-exo). The results demonstrate that f-exo effectively combines the osteolysis region-targeting capabilities of M2-exo with the bone metabolic homeostasis modulation effects of two exosomes (M2-exo and USC-exo), thereby achieving a significantly enhanced bone metabolic homeostasis targeting effect in the periprosthetic osteolysis region. The proteomic analysis of M2-exo, USC-exo, and f-exo revealed the potential mechanism of f-exo in targeting-regulation of bone metabolic homeostasis. Our study employs an innovative approach utilizing the fused exosome system for exosome targeted delivery, which offers a novel intervention strategy for the clinical management of periprosthetic osteolysis. Furthermore, it provides a novel conceptual framework for the development of exosome-based drug-targeting delivery systems. Scheme 1 (A) Preparation of f-exo. (B) Mechanism of f-exo for periprosthetic osteolysis target therapy through regulation of bone metabolic homeostasis. Scheme 1 (A) Preparation of f-exo. (B) Mechanism of f-exo for periprosthetic osteolysis target therapy through regulation of bone metabolic homeostasis. (Created with BioRender.com). We developed a novel fusion exosome (f-exo) system combining M2 macrophage-derived exosomes (M2-exo) and urine-derived stem cell exosomes (USC-exo) for targeted treatment of periprosthetic osteolysis by regulating the bone metabolic homeostasis, offered a new intervention strategy for managing periprosthetic osteolysis based on exosome-based drug delivery systems and broadened the scope for future research and therapeutic applications of exosomes.