Neupane Khaga R, Aryal Surya P, Harvey Brock T, Ramon Geraldine San, Chun Byeong, McCorkle J Robert, Kolesar Jill M, Kekenes-Huskey Peter M, Richards Christopher I
Department of Chemistry, University of Kentucky, Lexington, KY, 40506, USA.
Department of Cell and Molecular Physiology, Loyola University Chicago, Chicago, IL, 60153, USA.
Adv Healthc Mater. 2024 Dec;13(30):e2401906. doi: 10.1002/adhm.202401906. Epub 2024 Sep 6.
Tumor-associated macrophages (TAMs) represent the majority of the immune cells present in the tumor microenvironment. These macrophages exhibit an anti-inflammatory (M2)-like physiological state and execute immune-suppressive and tumor-supporting properties. With TAMs being plastic, there is a growing interest in reprogramming them toward a pro-inflammatory (M1)-like phenotype that exhibits anti-tumoral properties. Recent studies have demonstrated that both engineered vesicles derived from macrophages and endogenous extracellular vesicles produced by macrophages can be programmed to alter macrophage phenotype. Here it is demonstrated that pro-inflammatory macrophage-engineered subcellular vesicles (MEVs) have differential properties based on their organelle of origin. Endoplasmic reticulum specific MEVs (erMEVs) treated M2 macrophages exhibit enhanced pro-inflammatory cytokine production compared to plasma membrane specific MEVs (pmMEVs) treated M2 macrophages. In addition, under in vitro co-culture conditions, erMEVs elicit superior efficacy in suppressing the viability of cancer cells compared to the same concentration of pmMEVs. Furthermore, erMEVs and pmMEVs maintain differences in their membrane proteins, that regulate the repolarization efficacy of M2 macrophages toward an M1-like phenotype. In addition, The M2 to M1 repolarizing efficacy of MEVs can be altered by changing the activity of the membrane proteins present on erMEVs or pmMEVs.
肿瘤相关巨噬细胞（TAM）是肿瘤微环境中存在的大多数免疫细胞。这些巨噬细胞呈现出抗炎（M2）样生理状态，并具有免疫抑制和肿瘤支持特性。由于TAM具有可塑性，因此人们越来越有兴趣将它们重编程为具有抗肿瘤特性的促炎（M1）样表型。最近的研究表明，源自巨噬细胞的工程化囊泡和巨噬细胞产生的内源性细胞外囊泡都可以被编程来改变巨噬细胞表型。本文证明，促炎性巨噬细胞工程化亚细胞囊泡（MEV）因其起源细胞器的不同而具有不同特性。与经质膜特异性MEV（pmMEV）处理的M2巨噬细胞相比，经内质网特异性MEV（erMEV）处理的M2巨噬细胞表现出增强的促炎细胞因子产生。此外，在体外共培养条件下，与相同浓度的pmMEV相比，erMEV在抑制癌细胞活力方面具有更高的功效。此外，erMEV和pmMEV在其膜蛋白上存在差异，这些膜蛋白调节M2巨噬细胞向M1样表型的复极化功效。此外，通过改变erMEV或pmMEV上存在的膜蛋白的活性，可以改变MEV的M2至M1复极化功效。
