This study addresses the challenges of advanced non-small cell lung cancer (NSCLC) treatment, which remains highly morbid and mortal. Traditional treatments, including surgery, radiotherapy, chemotherapy, and immunotherapy, often face limitations such as drug resistance, severe side effects, and poor drug delivery. To overcome these challenges, the researchers developed a novel nanodelivery system, ICG@MnO2@Exo-anti-PD-L1 NPs, combining photodynamic therapy (PDT) and immunotherapy. The ICG@MnO2@Exo-anti-PD-L1 NPs consist of hollow manganese dioxide (MnO2) nanoparticles loaded with indocyanine green (ICG), a photosensitizer, and encapsulated in exosomes reprogrammed with PD-L1 monoclonal antibodies. This system is designed to target cancer cells expressing high levels of PD-L1, delivering anti-PD-L1 to the tumor site and activating T cell responses. Upon internalization by cancer cells, MnO2 catalyzes the conversion of hydrogen peroxide (H2O2) to oxygen (O2), alleviating tumor hypoxia. ICG then uses O2 to generate singlet oxygen (1O2) under near-infrared (NIR) irradiation, leading to tumor cell death. Additionally, high levels of H2O2 reduce MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further stimulating T cell responses. In vitro and in vivo experiments demonstrated that the ICG@MnO2@Exo-anti-PD-L1 NPs effectively targeted tumor sites, alleviated hypoxia, enhanced PDT efficiency, and induced macrophage polarization. In a mouse model of NSCLC, the NPs showed significant anti-tumor effects, reduced tumor growth, and inhibited metastasis. The system also demonstrated good biocompatibility and prolonged circulation time, making it a promising platform for multimodal therapy in NSCLC. This study highlights the potential of combining PDT with immunotherapy using precise drug delivery techniques to improve treatment outcomes for advanced NSCLC.This study addresses the challenges of advanced non-small cell lung cancer (NSCLC) treatment, which remains highly morbid and mortal. Traditional treatments, including surgery, radiotherapy, chemotherapy, and immunotherapy, often face limitations such as drug resistance, severe side effects, and poor drug delivery. To overcome these challenges, the researchers developed a novel nanodelivery system, ICG@MnO2@Exo-anti-PD-L1 NPs, combining photodynamic therapy (PDT) and immunotherapy. The ICG@MnO2@Exo-anti-PD-L1 NPs consist of hollow manganese dioxide (MnO2) nanoparticles loaded with indocyanine green (ICG), a photosensitizer, and encapsulated in exosomes reprogrammed with PD-L1 monoclonal antibodies. This system is designed to target cancer cells expressing high levels of PD-L1, delivering anti-PD-L1 to the tumor site and activating T cell responses. Upon internalization by cancer cells, MnO2 catalyzes the conversion of hydrogen peroxide (H2O2) to oxygen (O2), alleviating tumor hypoxia. ICG then uses O2 to generate singlet oxygen (1O2) under near-infrared (NIR) irradiation, leading to tumor cell death. Additionally, high levels of H2O2 reduce MnO2 to Mn2+, which remodels the immune microenvironment by polarizing macrophages from M2 to M1, further stimulating T cell responses. In vitro and in vivo experiments demonstrated that the ICG@MnO2@Exo-anti-PD-L1 NPs effectively targeted tumor sites, alleviated hypoxia, enhanced PDT efficiency, and induced macrophage polarization. In a mouse model of NSCLC, the NPs showed significant anti-tumor effects, reduced tumor growth, and inhibited metastasis. The system also demonstrated good biocompatibility and prolonged circulation time, making it a promising platform for multimodal therapy in NSCLC. This study highlights the potential of combining PDT with immunotherapy using precise drug delivery techniques to improve treatment outcomes for advanced NSCLC.