Photothermal-responsive Biomimetic Xenon Nanobubbles for Spatiotemporally Targeted Therapy of Ischemic Stroke.

Ischemic stroke (IS) involves persistent oxidative stress, exacerbated inflammation, and neuronal apoptosis. However, the therapeutic efficacy of current neuroprotective agents is severely restricted by the blood-brain barrier, which hinders their effective delivery to ischemic brain tissue. Although xenon (Xe) exhibits well-documented neuroprotective properties, its rapid diffusion and short in vivo retention limit its ability to match the evolving pathology of stroke. Therefore, developing Xe-based delivery systems with enhanced lesion targeting and controllable release is essential to fully harness the therapeutic potential of Xe for IS. Here, we developed macrophage membrane-coated Xe nanobubbles (Xe-MNBs), namely ADS 815EI@Xe-MNBs and IR 820@Xe-MNBs, which respectively carry lipophilic and hydrophilic photosensitizer analogues. Compared with IR 820@Xe-MNBs, ADS 815EI@Xe-MNBs exhibited a higher Xe payload, with a measured Xe content of 56.8 μL/mL. Combined in vivo and ex vivo fluorescence imaging demonstrated rapid brain-associated accumulation of the biomimetic nanobubbles within 5 min after intravenous administration. The cranial fluorescence signal of ADS 815EI@Xe-MNBs was approximately 3.2-fold higher than that of IR 820@Xe-MNBs, indicating a more pronounced early brain-associated fluorescence signal in the ischemic lesions. Upon near-infrared light irradiation, the photothermal effect triggered nanobubble disruption and Xe release in vitro, enabling externally controlled gas release. Treatment further attenuated oxidative damage and neuronal apoptosis while preserving neuronal integrity in the ischemic brain. Collectively, this work integrated inflammation-associated biomimetic targeting with photothermal-responsive Xe delivery, providing a promising strategy for spatiotemporally regulated gas therapy of IS. STATEMENT OF SIGNIFICANCE: 1. Phorbol 12-myristate 13-acetate (PMA)-induced differentiation of THP-1 cells was employed to construct biomimetic nanobubbles (NBs), endowing them with enhanced adhesion to inflamed endothelial cells and improved targeting of ischemic brain lesions. 2. By integrating fluorescence imaging with photothermal activation, spatiotemporally regulated delivery of xenon (Xe) was achieved, thereby enabling precise therapeutic intervention for ischemic stroke (IS). 3. Compared with the IR 820-based system, ADS 815EI-loaded, macrophage membrane-coated Xe nanobubbles (ADS 815EI@Xe-MNBs) exhibited a higher Xe-loading capacity, greater stability, and more pronounced brain accumulation at early time points, highlighting their potential for therapeutic intervention during the early treatment window after IS.