CD44‐Targeted Antioxidant Nanosheets Attenuate Pulmonary Fibrosis by Inhibiting the ROS‐STAT1‐CXCL10 Axis

Pulmonary fibrosis (PF) is a progressive and ultimately fatal lung disorder characterized by irreversible parenchymal scarring. Current therapeutic interventions are limited by suboptimal efficacy and significant adverse effects, highlighting a critical unmet need for the development of effective antioxidant therapeutic strategies. In this study, we engineered a novel nanotherapeutic platform composed of chondroitin sulfate (Chs)‐functionalized molybdenum disulfide nanosheets (CLM NSs) for targeted PF therapy. The system was synthesized through lipoic acid (LA)‐mediated conjunction of Chs to MoS ₂ nanosheets, significantly enhancing their physiological stability. CLM NSs utilize a CD44 receptor‐mediated targeting mechanism: initial pulmonary accumulation is achieved by attaching to circulating macrophages during the early inflammatory phase, followed by direct recognition of CD44 overexpressed on diseased alveolar epithelial cells in the late phase, enabling precise lesion‐specific accumulation. The nanosheets demonstrated robust broad‐spectrum antioxidant capacity, efficiently scavenging reactive oxygen/nitrogen species (ROS/RNS), restoring pulmonary redox homeostasis, and significantly inhibiting fibroblast activation and epithelial‐mesenchymal transition (EMT). In a bleomycin‐induced murine PF model, CLM NSs exerted significant therapeutic effects, markedly attenuating fibrotic progression, preserving alveolar architecture, and reducing pathological collagen deposition. Mechanistically, their therapeutic action involves inhibition of the critical ROS‐STAT1‐CXCL10 signaling axis, consequently suppressing macrophage recruitment and the inflammatory cascade. This nanoplatform, integrating efficient targeting, potent antioxidant activity, and excellent biocompatibility, represents a highly promising strategy for PF treatment.