银屑病是一种慢性炎症性疾病，其病因直接与皮肤免疫稳态失调有关。然而，如何精细调节皮肤免疫微环境以恢复稳态仍然是一个重要的挑战。受肿瘤外泌体在免疫逃逸中的自然属性的启发，肿瘤来源的外泌体作为有效治疗炎症性皮肤疾病的活性靶向纳米平台首次报道。由于角质细胞和免疫细胞在银屑病样皮肤炎症发作期间表达高水平的PD-1，因此产生了携带具有极强抗炎潜力的三叉叶毒甙的PD-L1阳性的黑色素瘤细胞衍生外泌体以治疗银屑病。对携带三叉叶毒甙的PD-L1+外泌体进行了表征，并进行了细胞摄取评估PD-1靶向能力。PD-L1+外泌体携带三叉叶毒甙的抗炎作用在银屑病的体外和体内模型中均得到了观察。我们的外泌体显著增加了CD4+ T细胞和角质细胞对三叉叶毒甙的摄取，显著抑制了Th17细胞的增殖，并促进Treg在银屑病样模型中的分化。显然，PD-L1+外泌体携带三叉叶毒甙通过对聚集在病变周围的CD4+ T细胞和角质细胞进行双重靶向，显著且安全地逆转了imiquimod（IMQ）诱导的小鼠银屑病，其表现为减少表皮厚度，减少斑块形成和抑制过度的炎症反应。我们设计的外泌体抑制了银屑病中的炎症细胞浸润和促炎细胞因子的产生。此外，PD-L1+外泌体携带三叉叶毒甙治疗减轻了银屑病皮肤中的铁死亡相关变化，从而减轻了过度炎症反应，并进一步减少了银屑病病变处角质细胞的异常增殖。该研究证明了我们设计的外泌体不仅可以作为针对银屑病治疗的治疗靶向策略，而且为炎症性疾病的临床应用提供了思路。

Psoriasis is a chronic inflammatory disease whose etiology is directly related to the dysregulation of cutaneous immune homeostasis. However, how to finely modulate the skin immune microenvironment to restore homeostasis remains an important challenge. Inspired by the natural attribute of tumor exosomes in the immune escape, the tumor-derived exosomes as an active targeting nanoplatform for the effective treatment of inflammatory skin disorder were first reported. As keratinocytes and immune cells express high PD-1 during the onset of psoriasiform skin inflammation, the PD-L1-positive exosomes derived from melanoma cells carrying pristimerin with extremely anti-inflammatory potential were yielded to treat psoriasis. The PD-L1+ exosomes carrying pristimerin were characterized, and the cellular uptake was performed to evaluate the PD-1 target capability. The anti-inflammatory action of PD-L1+ exosomes carrying pristimerin was observed in both in vitro and in vivo models of psoriasis. Our exosomes substantially increased pristimerin uptake with CD4+ T cells and keratinocytes, significantly inhibited the proliferation of Th17 cells, and promoted Treg differentiation in a psoriasis-like model. Obviously, PD-L1+ exosomes carrying pristimerin significantly and safely reversed imiquimod (IMQ)-induced psoriasis in mice, indicated by reducing epidermal thickness, decreasing plaque formation, and suppressed excessive inflammatory response, due to its dual targeting of both CD4+ T cells and keratinocytes gathering around the lesion. The inflammatory cell infiltration and pro-inflammatory cytokine production in psoriasis were suppressed by our engineered exosomes. Besides, PD-L1+ exosomes carrying pristimerin treatment alleviated ferroptosis-related changes in psoriatic skin, thereby dampening excessive inflammation and, in turn, decreasing the abnormal proliferation of keratinocytes in psoriatic lesions. This study demonstrates that our engineered exosomes can not only act as a treat-to-target strategy for psoriasis treatment but also provide insight in clinical application of inflammatory disorders.