Tumor-derived PD-L1 + exosomes with natural inflammation tropism for psoriasis-targeted treatment

Abstract Background: Psoriasis is a chronic and readily recurrent inflammatory skin disease. To date, there is no cure for psoriasis and significant challenges remain in developing more safe and efficacious novel targeted therapies. Psoriasis is characterized by abnormal activation of the immune system, and hyperproliferation and aberrant differentiation of keratinocytes. Psoriatic keratinocytes death is also recently recognized as a major amplifier to the initiation of inflammatory cascade. Given that both keratinocytes and immune cells express high PD-1 in psoriasis, which imply PD-1 as a potential therapeutic target for psoriasis. Here, we developed a well-structured pristimerin nanodot-loaded PD-L1 positive exosome derived from tumor cells (Pri@exo) and elucidated their targeting therapeutic effects. Results: The Pri@exo displays strong cellular uptake and intracellular retention in active CD4+ T cells and HaCaT keratinocytes, suggesting the PD-1+ cells targeting capacity of Pri@exo. Remarkably, Pri@exo significantly and safely reversed imiquimod (IMQ)-induced psoriasis in mice, indicated by reducing epidermal thickness, decreasing plaque formation, and over-activating inflammation since it targeted both CD4+ T cells and keratinocytes gathering around the lesion. The increasing inflammatory cytokine excretion of CD4+ T cells in psoriasis was suppressed by Pri@exo. Besides, Pri@exo treatment alleviated ferroptosis-related changes in psoriatic skin, thereby dampening excessive inflammation and, in turn, decreasing the abnormal proliferation of keratinocytes in psoriatic lesions. Conclusion: This tumor-derived PD-L1+ exosomes has a natural inflammatory tropism and excellent anti-inflammatory effect, and able to act as a bio-inspired nanocarrier for various therapeutic agents to optimized inflammatory disease therapy.