A GGT‐Activatable Chiral Gadolinium Polymer Probe for Dual‐Modal MR/NIRF Imaging of Glioma

ABSTRACT Magnetic resonance imaging (MRI) offers noninvasive, radiation‐free anatomical imaging but is inherently constrained by poor sensitivity for molecular event detection. To address this, we present PAA‐Gd‐ γ ‐GT , an enzyme‐activatable dual‐modal probe that synergizes MRI's anatomical precision with the exceptional sensitivity of near‐infrared fluorescence (NIRF). The probe integrates a chiral Gd‐DOTA complex featuring optimized water‐exchange kinetics, a poly(acrylic acid) (PAA) scaffold for relaxivity enhancement, and a γ ‐glutamyl‐caged NIRF fluorophore for tumor‐selective activation. The probe exhibits a remarkable baseline relaxivity ( r 1 ) of 16.1 mM −1 s −1 , which further increases to 21.3 mM −1 s −1 upon GGT‐mediated cleavage and subsequent albumin binding, a nearly sevenfold enhancement over clinically used Gd‐DOTA (3.0 mM −1 s −1 ). Notably, postactivation intermediates enable prolonged retention within orthotopic gliomas via interaction with local biomolecules, ensuring sustained contrast without compromising biocompatibility. This design affords concurrent tumor delineation via T 1 ‐weighted MRI and molecular validation via NIRF, establishing a robust, enzyme‐responsive multimodal platform with translational potential for glioma margin identification and image‐guided surgery.