Multifunctional Nanoparticles for Imaging-Guided Tumor Phototherapy via ONOO- Mediated Tumor Microenvironment Remodeling

Abstract The highly condensed extracellular matrix characteristic of tumor tissues significantly impedes the transport and accumulation of fluorescent probes and therapeutic drugs, ultimately compromising the accuracy of tumor detection and the effectiveness of therapeutic interventions. Different from conventional fluorescence imaging, afterglow imaging is characterized by long-lasting luminescence that persists following the cessation of external photoexcitation, which has earned it increasing research attention in the field of biomedical imaging. However, currently reported afterglow probes generally suffer from weak luminescence signals and complicated component compositions. To address these issues, a multifunctional nanoparticle, mMB@DPA has been designed and constructed by self-assembling a photosensitizer with l-arginine loaded onto DSPE-PEG2000-NH2. The resulting nanoparticles possess multiple functions, including hydrogen peroxide-responsive nitric oxide (NO) release, afterglow imaging, pronounced reactive oxygen species (ROS) generation capability and excellent photothermal conversion efficiency, enabling fluorescence-guided tumor visualization during phototherapy. In response to elevated intracellular hydrogen peroxide or ROS generated upon light irradiation, mMB@DPA rapidly produces abundant NO on its surface. Upon 660 nm laser irradiation, the nanoparticles concurrently produce ROS and hyperthermia. The generated ROS further reacts with NO to form peroxynitrite (ONOO−), a potent oxidative and nitrative mediator. ONOO− generation not only upregulates matrix metalloproteinase (MMP) expression to facilitate nanoparticle penetration and tumor accumulation, but also inhibits heat-shock protein (HSP) expression, which potentially diminishes the thermotolerance of tumor cells. Using a subcutaneous tumor model, we verified that ONOO−-mediated synergistic phototherapy achieves markedly improved antitumor therapeutic efficacy.