Microenvironment-activatable nanoagent for real-time NIR-II monitoring and targeted therapy of arterial restenosis

Arterial restenosis is a critical risk factor for life-threatening cardiovascular diseases. Precise intervention and real-time monitoring are extremely important but remain major clinical challenges. Here, we present an advanced theranostic nanoagent that integrates hypoxia-responsive second near-infrared (NIR-II) fluorescence imaging with hypoxia-activatable anti-proliferative therapy for real-time diagnostics and precision treatment. This nanoplatform is constructed by co-encapsulating a novel N-oxide-based molecular probe and a hypoxia-activatable prodrug tirapazamine (TPZ) into osteopontin (OPN)-targeted liposomes. Under hypoxic conditions, the N-oxide probe undergoes conversion to its amine derivative, altering the intramolecular charge transfer properties and triggering turn-on NIR-II fluorescence signal. This property enables high-sensitivity, real-time monitoring of restenosis lesions in vivo. The nanoplatform exhibits dual hypoxia-responsive functionality: TPZ is selectively activated in hypoxic vascular lesions to inhibit vascular smooth muscle cell proliferation, and sustained OPN-mediated targeting promotes vascular repair. In guidewire-induced restenosis models, this system achieves simultaneous real-time monitoring of lesion progression via NIR-II imaging and significantly reduce restenosis while enhancing re-endothelialization. This study offers a promising strategy for developing high-performance theranostic nanoplatforms, enabling precise detection and improved treatment of restenosis-related diseases.