BACKGROUND: Nonsurgical and minimally invasive approaches for early-stage peripheral lung cancer are needed to avoid the known morbidity of surgical resection, particularly in high-risk patients. We previously demonstrated the utility of multifunctional porphyrin-phospholipid nanoparticles (porphysomes) for fluorescence imaging and phototherapy after preferential accumulation into tumors. The objective of this study was to demonstrate the feasibility of porphysome-mediated imaging and photothermal therapy using a newly developed fiberscope and thoracoscope. METHODS: To prepare this technology for clinical translation, we developed a porphysome-specific fiberscope (scanning fiber endoscope and porphysome-specific thoracoscope), both capable of detecting porphysome fluorescence, for image-guided transbronchial and transpleural photothermal therapy to treat endobronchial/peribronchial and subpleural tumors, respectively. These were tested in three animal models: human lung cancer xenografts (A549) in mice, orthotopic VX2 lung tumors in rabbits, and ex vivo pig lung into which A549 tumor tissue was transplanted. RESULTS: The scanning fiber endoscope, with a 1.2-mm diameter, is small enough to pass through the working channel of a conventional bronchoscope and could visualize porphysome-laden tumors located inside or close to the peripheral bronchial wall. The porphysome-specific thoracoscope system had high sensitivity for porphysome fluorescence and enabled image-guided thoracoscopic resection of porphysome-accumulating tumors close to the pleura. Porphysomes also enhanced the efficacy of scanning fiber endoscope-guided transbronchial photothermal therapy and porphysome-specific thoracoscope-guided transpleural photothermal therapy, resulting in selective and efficient tumor tissue ablation in the rabbit and pig models. CONCLUSIONS: These results support the potential for clinical translation of this novel platform to affect nonsurgical and minimally invasive treatment options for early-stage peripheral lung cancer.