Microenvironment-Triggered Signal Amplification for Dual-Modal Fluorescence/MRI of Hepatocellular Carcinoma.

Abstract

Dual-modal fluorescence/magnetic resonance imaging (FL/MRI) offers sensitive and high-resolution detection of hepatocellular carcinoma (HCC), but its effectiveness is often limited by weak signal synergy and poor responsiveness to the tumor microenvironment. Here, we report a tumor-microenvironment-responsive nanoprobe, TCM-Gd-P NPs, designed to remain initially signal-silent, as amphiphilic polymer encapsulation sequesters the aggregation-induced emission luminogen (TCM-4COOLi) and restricts water interaction with Gd³⁺ ions, effectively quenching fluorescence and reducing longitudinal relaxivity. Under acidic tumor conditions, protonation of the polymer matrix restricts intramolecular motion of TCM-4COOLi, triggering up to a 12.4-fold fluorescence enhancement at 584 nm, while TCM-4COOGd complexes increase water proton accessibility, producing an ∼8.0-fold increase in longitudinal relaxivity and spatially coupled MRI signal amplification. <i>In vivo</i>, TCM-Gd-P NPs achieved 4.2-fold fluorescence and 3.3-fold MRI contrast enhancement in tumors relative to adjacent tissue, enabling molecular-level delineation of tumor margins via fluorescence imaging and high-resolution anatomical mapping via MRI. Importantly, by applying both modalities to the same orthotopic HCC mice, the high sensitivity of fluorescence imaging effectively corroborated the deep-tissue anatomical resolution provided by MRI. This work establishes a microenvironment-triggered, orthogonal signal amplification strategy for FL/MRI, providing a generalizable framework for intelligent solid-tumor diagnostics.