Wu Qianyi, Liu Shuyun, Zhao Meng, Wang Yizhuo, Lv Ke, Zhu Jiaying, Liu Jingping
Department of General Surgery and NHC Key Laboratory of Transplant Engineering and Immunology, Frontiers Science Center for Disease-related Molecular Network, West China Hospital of Sichuan University, No. 2222 Xinchuan Road, Chengdu 610041, China.
Department of Emergency, Guizhou Provincial People's Hospital, Guiyang, China.
Biomater Sci. 2025 May 13;13(10):2690-2703. doi: 10.1039/d4bm01505c.
Uncontrolled inflammation is one of the major causes of various forms of tissue injury, and nanomedicines with immunoregulatory effects are needed. Mesenchymal stromal cell-derived extracellular vesicles (, MSC-EVs) have been proposed as promising therapies, but the highly efficient generation of EVs with desirable properties is still a considerable challenge in this field. Here, we report that preconditioning MSCs with a critical immune process (pyroptosis) is a robust method for improving both the yield and anti-inflammatory potency of MSC-EVs. In brief, pyroptosis-preconditioned MSCs using a combined lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulation showed elevated EV yields compared with those of MSCs cultured under normal conditions. Pyroptosis preconditioning upregulated multiple pathways (, cell proliferation, DNA repair, and the immune response) in MSCs, leading to the enrichment of immunoregulatory cargos (, PD-L2 and STC2) in MSC-EVs. , pyroptosis-preconditioned MSC-EVs (P-EVs) treatment has greater potential to suppress cytokine expression and cell death in pyroptotic macrophages than treatment with normal MSC-EVs (N-EVs). Compared with N-EV treatment, P-EV treatment showed superior potency in attenuating proinflammatory cell infiltration, cytokine/chemokine expression, resident tissue cell death, and the severity of pathological injury in different models of inflammatory diseases (acute lung or kidney injury), and these effects are likely the joint result of diverse functional cargos delivered by such EVs. This study highlights that pyroptosis preconditioning is a promising strategy for the highly efficient production of MSC-EVs with advanced therapeutic potential for treating diverse inflammatory diseases.
不受控制的炎症是各种组织损伤的主要原因之一，因此需要具有免疫调节作用的纳米药物。间充质基质细胞衍生的细胞外囊泡（MSC-EVs）已被认为是有前景的治疗方法，但高效生成具有理想特性的细胞外囊泡在该领域仍然是一个巨大的挑战。在此，我们报告用关键免疫过程（细胞焦亡）预处理间充质基质细胞是提高MSC-EVs产量和抗炎效力的有效方法。简而言之，与在正常条件下培养的间充质基质细胞相比，使用脂多糖（LPS）和三磷酸腺苷（ATP）联合刺激进行细胞焦亡预处理的间充质基质细胞显示出更高的细胞外囊泡产量。细胞焦亡预处理上调了间充质基质细胞中的多种途径（如细胞增殖、DNA修复和免疫反应），导致MSC-EVs中免疫调节货物（如PD-L2和STC2）的富集。因此，与正常MSC-EVs（N-EVs）处理相比，细胞焦亡预处理的MSC-EVs（P-EVs）处理在抑制焦亡巨噬细胞中的细胞因子表达和细胞死亡方面具有更大的潜力。与N-EV处理相比，P-EV处理在减轻不同炎症疾病模型（急性肺或肾损伤）中的促炎细胞浸润、细胞因子/趋化因子表达、驻留组织细胞死亡和病理损伤严重程度方面显示出更强的效力，这些作用可能是此类细胞外囊泡递送的多种功能货物的共同结果。这项研究强调，细胞焦亡预处理是一种有前景的策略，可高效生产具有治疗多种炎症疾病先进治疗潜力的MSC-EVs。
