Cellular nanovesicles with bioorthogonal targeting enhance photodynamic/photothermal therapy in psoriasis

The interaction between over-proliferating keratinocytes and excessive activated immune cells contributes to the development and progression of psoriasis. Photodynamic therapy (PDT)/photothermal therapy (PTT) is a promising method to treat skin diseases due to their synergistic effect and low side effect. Cell membrane is an ideal cell-mediated drug delivery platform with inherent biocompatibility, but lacks of specific targeting properties to increase drug accumulation in the psoriatic site. Here, we develop a new PDT/PTT strategy to treat psoriasis, based on cell membrane functionalization by metabolic glycoengineering with unnatural sugars, which label cell membranes with chemical tags for subsequent targeting. In our study, in order to enhance the PDT/PTT effect, N₃-labeled cell membrane-derived nanovesicles coated with IR-780 nanoparticals (N₃-NV-INPs) are constructed, which can specifically recognize DBCO-modified psoriatic lesions through bioorthogonal click chemistry to achieve targeted PDT/PTT effect. The results showed that N₃-NV-INPs could specifically target the psoriatic lesions, enhance the synergistic effect of PDT/PTT under the irradiation of near-infrared light, exhaust excessive proliferation of keratinocytes, regulate immunity, reduce the release of cytokines, such as IL-17, IL-22, TNF-α, improve epidermal hyperplasia, and effectively relieve the symptoms of psoriasis. Taken together, we constructed cellular nanovesicles based on an alternative artificial targeting strategy to enhance PDT/PTT effect in psoriasis, which shows great potential in clinical application. STATEMENT OF SIGNIFICANCE: The major challenge in the treatment of psoriasis is how to effectively deliver drugs to the lesions to exhaust overproliferating keratinocytes and modulate immunity. A newly-developed cell membrane-coating technology combined with biorthogonal targeted delivery promotes more drug accumulation at the lesions of the disease. Incorporation of an effective photosensitizer into the lesions of psoriasis site results in exert PDT/PTT effect under the irradiation of near-infrared light. The synergistic PDT/PTT effect can effectively exhaust keratinocytes and immune cells in the epidermis and dermis, reduce the release of inflammatory cytokines, and relieve the symptoms of psoriasis. This unique functional cell membrane nanovesicles combined with bioorthogonal targeting is applied to enhance the PDT/PTT effect in psoriasis and may provide a solution for the clinical treatment of other inflammatory skin diseases.