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Melanoma is resistant to chemotherapeutics with poor prognosis and high potential of metastasis. Photodynamic therapy (PDT) represents a localized therapeutic modality, as cytotoxicity occurs when light activates photosensitizer (PS) at the tumour site. The aim of this study is dermal delivery of a high molecular weight hydrophilic photosensitizer (PS), ferrous chlorophyllin (Fe-CHL) via transethosomes for treatment of melanoma by PDT.Transethosomes were made of phosphatidyl choline, edge activator and 20%w/v Ethanol. They were evaluated for mean size, zeta potential, entrapment efficiency, ex-vivo permeation, localization in skin layers by transmission electron microscope (TEM), and finally, evaluated in melanoma animal model. Transethosomes of different mean vesicle size were evaluated for their skin retention and permeation through mice skin. TE of ˜500nm (E3) being ultradeformable showed deep localization in skin confirmed by ex-vivo and TEM micrographs without permeation of PS to recipient compartment due to its size.The proposed study offers successful treatment of resistant melanoma by PDT, where complete tumour regression of small tumours occurred after single PDT, while large tumours after double PDT without recurrence for 8months. This indicates the efficiency of nanovesicles in PS delivery and the efficiency of Fe-CHL in production of reactive oxygen species.