ALP‐Responsive Luminescent Nanosheets Promote Precise Hepatitis Theragnostic by Co‐Targeting NLRP3 and Cholestasis

Cholestatic hepatitis is a progressive inflammatory liver disease characterized by disrupted bile acid homeostasis, excessive reactive oxygen species (ROS) generation, and chronic inflammation, remains clinically challenging due to limited diagnostic precision and lack of effective, targeted therapies. Here, we developed a multifunctional theranostic nanoplatform, CyP-CuGA-UDCA nanosheets (NSs), that integrates therapeutic intervention with enzyme-responsive disease monitoring. The platform features copper-gallic acid (CuGA) nanozymes with superoxide dismutase-, peroxidase-, and catalase-like activities for effective ROS scavenging and NLRP3 inflammasome inhibition. Co-loaded with ursodeoxycholic acid (UDCA) to alleviate bile acid toxicity, and with an alkaline phosphatase (ALP)-responsive near-infrared fluorescent probe (CyP), the nanoplatform enables targeted treatment and real-time imaging of cholestatic lesions. In a DDC-induced mice model, CyP-CuGA-UDCA NSs significantly suppressed pro-inflammatory cytokine production, reduced hepatic macrophage infiltration, attenuated oxidative stress and hepatocyte apoptosis, and alleviated fibrosis, outperforming monotherapies. Concurrently, the ALP-activated fluorescence allowed precise visualization of cholestatic progression in vivo. This study presents a first-in-class nanostructured system that couples NLRP3 inflammasome modulation and bile acid regulation with enzyme-specific diagnostics, offering a robust strategy for precision therapy and monitoring of cholestatic hepatitis.