In the present work biocompatible quercetin and curcumin nanovesicles were developed as a novel approach to prevent and restore skin tissue defects on chronic cutaneous pathologies. Stable and suitable quercetin- and curcumin-loaded phospholipid vesicles, namely liposomes and PEVs (Penetration Enhancer-containing Vesicles), were prepared. Vesicles were made from a highly biocompatible mixture of phospholipids and alternatively a natural polyphenol, quercetin or curcumin. Liposomes were obtained by adding water, while PEVs by adding polyethylene glycol 400 and Oramix(®)CG110 to the water phase. Transmission Electron Microscopy, cryogenic-Transmission Electron Microscopy, and Small- and Wide-Angle X-ray Scattering showed that vesicles were spherical, oligo- or multilamellar and small in size (112-220 nm). In vitro and in vivo tests underlined a good effectiveness of quercetin and curcumin nanovesicles in counteracting TPA (phorbol ester) induced lesions and inflammation. Myeloperoxydase activity, used to gauge inflammation, was markedly inhibited by quercetin liposomes (59%) and curcumin liposomes and PEG-PEVs (∼68%). Histology showed that PEG-PEVs provided an extensive reepithelization of the TPA-damaged skin, with multiple layers of thick epidermis. In conclusion, nanoentrapped polyphenols prevented the formation of skin lesions abrogating the various biochemical processes that cause epithelial loss and skin damage.