Molecular-gated MRI via α_IIbβ₃: ligand-triggered relaxation switching for efficient imaging of activated...

Effective management of thromboembolic diseases is critically limited by the absence of imaging tools that can distinguish biologically active thrombi from inactive clots, thereby impeding personalized therapeutic strategies. To address this, we designed a molecular-gated magnetic resonance imaging (MRI) probe that converts the specific binding event between a fibrinogen-mimetic ligand and activated platelet integrin α_IIbβ₃ into a bright T1 signal. Mimicking the natural fibrinogen, our fibrinogen-mimetic nanovesicle probe (denoted as H12-PEG-Gd-NV) is engineered with the specific H12 peptide, a fibrinogen γ-chain-derived dodecapeptide (HHLGGAKQAGDV, H12), to target α_IIbβ₃. Its diagnostic signal is switched "on" exclusively by binding to the active conformation of α_IIbβ₃ on activated platelets at a thrombus site, which defines the ligand-triggered relaxation switching mechanism. This provides a high contrast relative to conventional "always-on" agents, which lack target-dependent signal control. Microfluidic assays confirmed the specific binding of H12-PEG-Gd-NV to α_IIbβ₃ on activated platelets under physiological shear flow. In vivo, this molecular-gated imaging strategy enabled high-contrast visualization of thrombi in both carotid artery thrombosis and cerebral thromboembolism models, with the probe exhibiting prolonged circulation and precise accumulation at thrombotic sites. Comprehensive toxicological evaluations revealed a favorable biosafety profile, with no significant adverse effects observed across platelet function, hematological, biochemical, coagulation, and histopathological analyses. By directly imaging α_IIbβ₃ status, this molecular-gated MRI approach fulfills a critical unmet need for noninvasive thrombus detection and holds strong potential to guide personalized antithrombotic therapy.