Differential Sequestration and Release in a Single Nanoplatform Enables On‐Demand Theranostics for Liver Fibrosis

ABSTRACT The clinical management of liver fibrosis is hindered by the inability of conventional biopsies to map lesions spatially and the lack of sensitive, theranostic agents for early detection and intervention. Here, we introduce a polydopamine (PDA)‐based nanoplatform embodying a conceptually distinct strategy: differential sequestration and release within a single system. Upon encountering fibrosis severity‐dependent elevated H 2 O 2 in fibrotic liver microenvironment, a manganese carbonyl complex (Mn(CO) 5 Br) incorporated in the nanostructure decomposes to simultaneously generate Mn 2+ and carbon monoxide (CO). PDA plays a dual regulatory role: it strongly traps Mn 2+ via coordination bonds, enhancing T 1 relaxivity for high‐contrast magnetic resonance imaging (MRI), while releasing CO in a controlled manner to exert anti‐fibrotic and anti‐inflammatory effects. This “capture‐and‐release” design enables spatiotemporally coordinated diagnosis and therapy. The nanoprobe allows precise stratification of fibrosis stages through MRI signal intensity that correlates with collagen deposition and supports 3D reconstruction of lesion distribution. Concurrently, released CO attenuates fibrotic progression by modulating the TGF‐β1/Smad pathway, scavenging reactive oxygen species (ROS), and promoting macrophage repolarization, all without inducing systemic toxicity. This work demonstrates that differential molecular control within one nanoplatform can synchronize imaging‐guided diagnosis with targeted microenvironment reprogramming, offering a translatable strategy for liver fibrosis theranostics.