Multienzymatic hybrid bio-heterojunction for synergistic microenvironment reprogramming and selenoprotein-activated mitochondrial bioenergetics in diabetic osseointegration

Regeneration of diabetic bone defects has always been a significant challenge in clinical treatment. The pathologic diabetic microenvironment, characterized by bacterial infection, excessive reactive oxygen species (ROS) generation, lactate accumulation, and chronic inflammation, triggers mitochondrial dysfunction and an energy metabolism crisis. To address this issue, we developed a synergistic multienzymatic bio-heterojunction (MoSe2/PtCu@LOx) by integrating molybdenum diselenide (MoSe2) nanosheets with platinum-copper (PtCu) nanoparticles and lactate oxidase (LOx) as a self-cyclic cascade catalysis system. The MoSe2/PtCu Schottky heterojunction enables NIR-responsive photothermal and photodynamic antibacterial activity, while self-cyclic cascade catalysis of PtCu and LOx effectively eliminates excessive ROS and accumulated lactate, thereby ameliorating the pathologic diabetic microenvironment. Crucially, the released selenium species activates SIRT3 signaling, upregulating Gpx1 expression and stabilizing mitofusin 2 (Mfn2), which enhances mitophagic flux and restores mitochondrial bioenergetics. As a result, the MoSe2/PtCu@LOx can synergistically ameliorate the pathologic microenvironment and mitochondrial dysfunction, thereby effectively restoring energy metabolism function and promoting infected diabetic bone regeneration. This multienzymatic hybrid bio-heterojunction provides a metabolic-oriented therapeutic nanoplatform for diabetic bone regeneration.