Chemical Gambit in Bone Microenvironment: pH-Responsive Cu–Mn Nanoplatform Breaks the Inflammation-Osteoclast Vicious Cycle in Prosthesis-Associated Osteolysis

Prosthesis-associated osteolysis (PAO), driven by a self-perpetuating inflammatory-osteoclastogenic cycle, remains a critical challenge following arthroplasty. Current single-target therapies inadequately address the spatiotemporal heterogeneity of pathological microenvironments: ROS overload during the early immune activation phase and low pH in the osteoclastic resorption phase. This study develops bovine serum albumin (BSA)-coated copper-manganese carbonate nanocomposites (CuMnCO₃@BSA, CMC) that dynamically coordinate immunosuppressive intervention with osteoclast-specific cuproptosis induction through microenvironment-guided functional switching. <i>In vitro</i> studies demonstrate that at neutral pH, Mn²⁺-mediated SOD/CAT-like nanozyme activity effectively scavenges ROS and reprograms macrophage metabolism to oxidative phosphorylation, thereby suppressing M1 polarization. During late osteoclast differentiation, acid-triggered carbonate decomposition releases Cu²⁺, selectively eliminating mature osteoclasts via cuproptosis-mediated mitochondrial lipoylated protein aggregation and TCA cycle collapse. In titanium particle-induced osteolysis models, this dual-functional CMC strategy demonstrates superior therapeutic efficacy to bisphosphonates. This study pioneers a microenvironment-adaptive nanotherapeutic approach, innovatively coupling cuproptosis with immune-metabolic regulation, thereby establishing a novel paradigm for osteolytic disease management.