Molybdenum-bridged endo-exogenous antioxidant synergy reverses acute kidney injury via mitochondrial homeostasis reconstruction

Acute kidney injury (AKI) progression is driven by mitochondrial redox collapse in proximal tubular epithelial cells (PTECs), where reactive oxygen species (ROS) surge and molybdenum (Mo) metabolic dysregulation create an “oxidative storm-defense collapse” cycle. Conventional antioxidant therapies fail to halt AKI chronicity due to their inability to restore Mo-dependent detoxification enzymes (e.g., Mo-containing Amidoxime Reducing Component, mARC). To address this dual pathology, we developed N-acetylcysteine (NAC)-modified molybdenum disulfide quantum dots (NMDs) that implement an endo-exogenous antioxidant collaborative strategy, synergizing exogenous ROS elimination with endogenous Mo enzyme restoration. NMDs achieve triple-tiered targeting: 1) Organ-selective accumulation leveraging NMDs' hydrophilicity and ultrasmall size; 2) Cell-specific internalization through Organic Anion Transporter 1 (OAT1)-mediated active uptake into PTECs; 3) Mitochondrial precision delivery guided by NAC's intrinsic mitochondrial affinity. Within pathological microenvironments, NMDs exhibit multidimensional therapeutic superiority: exposed Mo(Ⅳ) directly quenches mitochondrial ROS via electron transfer (external clearance), while released Mo ions reactivate mARC and NAC supplies glutathione precursors, synergistically rebuilding endogenous antioxidant defenses (internal reinforcement). In vivo validation demonstrated NMDs’ superior therapeutic efficacy, outperforming clinical antioxidant NAC. This work pioneers a “scavenging-fortification” strategy through Mo-centric metabolic regulation and nanotechnology integration, validating Mo-based materials' therapeutic potential and establishing a paradigm for mitochondrial-targeted AKI treatment. • Through constructing N-acetylcysteine-functionalized molybdenum disulfide quantum dots (NMDs), this nanoplatform achieves hierarchical mitochondria-targeted delivery, synergistically restoring redox homeostasis and offering a novel therapeutic paradigm for mitochondrial injury-related diseases like acute kidney injury. • NMDs achieve triple-tiered targeting (kidney .→ proximal tubular cells → mitochondria) via OAT1-mediated uptake and mitochondrial protein affinity, overcoming renal delivery barriers. • NMDs synergistically eliminate mitochondrial reactive oxygen species (ROS) via Mo(IV)/Mo(VI) valence transition and restore endogenous defenses by supplying Mo cofactors for mARC reactivation and NAC-derived GSH precursors. • NMDs (2 mg/kg) reverse AKI in rhabdomyolysis models, reducing serum creatinine and tubular injury scores, outperforming clinical antioxidants NAC. • By preserving mitochondrial integrity, NMDs inhibit mtDNA leakage, suppressing cGAS-STING-driven inflammation and intrinsic apoptosis.