Cell membrane-encased thylakoid as white light triggered PDT therapy for facile and targeted choroidal melanoma treatment

Choroidal melanoma, the most prevalent subtype of uveal melanoma with a bleak prognosis, necessitates safer and more efficient treatment methods. Tumor cell membrane-modified nanodelivery systems have exhibited significant enhancement in photodynamic therapy (PDT). Currently, photosensitizers utilized in PDT encompass porphyrin-related organic molecules and other types, requiring complex and intricate systems construction. This study focuses on harnessing the naturally occurring photodynamic active photosynthetic unit-thylakoid which serve as a major source of singlet oxygen. Initially, thylakoids extracted from fresh leaves were identified based on their absorbance value, morphology, and characteristic proteins. The tumor cell membrane-thylakoid membrane (CM-Thy) photodynamic therapy system was prepared through ultrasonic fragmentation and liposomal extrusion technology. Due to its membrane targeting ability, CM-Thy demonstrated excellent uptake performance towards OCM-1 cells within intraocular tissues. Both in vitro and in vivo experiments confirmed CM-Thy's photodynamic activity. Specifically, Thy in the system generates singlet oxygen, after cellular internalization, the elevated intracellular reactive oxygen species (ROS) triggered by this process induce cell lipid peroxidation and increased membrane permeability, while singlet oxygen further mediates DNA oxidative damage, reduced cell proliferation capacity, and NLRP3 inflammasome-mediated pyroptosis, all these effects synergistically contribute to ultimate tumor cell apoptosis. Furthermore, the anti-tumor effect of CM-Thy was validated through various mechanisms involved in tumor formation such as angiogenesis and vasculogenic mimicry. Interestingly, the results from visible light experiments conducted in vitro also substantiated the remarkable therapeutic efficacy of this system for refractive eye disorders while providing innovative ideas for cross-species biological interventions. The nanocomposites of cell membrane-thylakoid (CM-Thy) are prepared through extrusion from the mixture of spinach's thylakoids and tumor cells' membranes. Injection of the membrane complexes into the subretinal space has demonstrated remarkable therapeutic effects in treating choroidal melanoma. In this process of tumor eradication, the cell membrane facilitates targeted uptake of the complex, while the photodynamic therapeutic property of thylakoid is activated by visible light, including daily light sources, leading to inhibitory effects on various mechanisms involved in tumor formation. • A biomimetic photodynamic therapy (PDT) system (CM-Thy) was constructed by fusing tumor cell membranes (CM) with plant-derived thylakoids (Thy), enabling homologous targeting and efficient PDT for choroidal melanoma. • Thy in CM-Thy generates abundant singlet oxygen ( 1 O 2 ) upon white light or 660 nm laser irradiation, inducing tumor cell apoptosis via dual mechanisms: direct DNA oxidative damage and NLRP3 inflammasome-mediated pyroptosis. • CM-Thy inhibits choroidal melanoma progression by targeting multiple tumorigenic mechanisms, including angiogenesis, vasculogenic mimicry, cell migration, and 3D tumor spheroid formation. • Activation of CM-Thy by natural daily light provides a mild, non-invasive therapeutic strategy, opening new avenues for cross-species biological interventions in ocular tumors.