Jia Honglin, Liu Tao, Yang Qunfang, Zheng Haiping, Fu Shixiang, Hong Jiahui, Zhou Zechen, Huang Qingshan, Zhang Zhaowei, Zhang Haigang, Chen Xiaohong, Sun Renshan, Shan Wenjun
College of Pharmacy, Army Medical University, Chongqing 400038, PR China.
Department of Dermatology, Daping Hospital, Army Medical University, Chongqing 400038, PR China.
Bioconjug Chem. 2023 Apr 10. doi: 10.1021/acs.bioconjchem.3c00129.
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 and 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.
银屑病是一种慢性炎症性疾病，其病因与皮肤免疫稳态的失调直接相关。然而，如何精细调节皮肤免疫微环境以恢复稳态仍然是一项重大挑战。受肿瘤外泌体在免疫逃逸中的天然属性启发，首次报道了肿瘤来源的外泌体作为一种活性靶向纳米平台用于有效治疗炎症性皮肤病。由于角质形成细胞和免疫细胞在银屑病样皮肤炎症发作期间高表达PD-1，因此产生了携带具有极强抗炎潜力的原百部素的黑色素瘤细胞来源的PD-L1阳性外泌体来治疗银屑病。对携带原百部素的PD-L1外泌体进行了表征，并进行了细胞摄取实验以评估其对PD-1的靶向能力。在银屑病的体内和体外模型中均观察到了携带原百部素的PD-L1外泌体的抗炎作用。在银屑病样模型中，我们的外泌体显著增加了原百部素对CD4 T细胞和角质形成细胞的摄取，显著抑制了Th17细胞的增殖，并促进了Treg分化。显然，携带原百部素的PD-L1外泌体显著且安全地逆转了咪喹莫特（IMQ）诱导的小鼠银屑病，表现为表皮厚度降低、斑块形成减少以及过度炎症反应受到抑制，这是由于其对聚集在病变周围的CD4 T细胞和角质形成细胞具有双重靶向作用。我们构建的外泌体抑制了银屑病中的炎性细胞浸润和促炎细胞因子的产生。此外，携带原百部素的PD-L1外泌体治疗减轻了银屑病皮肤中与铁死亡相关的变化，从而抑制了过度炎症，进而减少了银屑病病变中角质形成细胞的异常增殖。这项研究表明，我们构建的外泌体不仅可以作为银屑病治疗的靶向治疗策略，还为炎症性疾病的临床应用提供了思路。
