Glucocorticoids are well established anti-inflammatory agents, however, their use to treat chronic inflammatory diseases is limited due to a number of serious side effects. For example, long-term local treatment of chronic wounds with glucocorticoids is prohibited by dysregulation of keratinocyte and fibroblast function, leading to skin thinning. Here, we developed and tested liposome formulations for local delivery of dexamethasone to primary human macrophages, to drive an anti-inflammatory/pro-resolution phenotype appropriate for tissue repair. The liposomes were loaded with the pro-drug dexamethasone-phosphate and surface-modified with either polyethylene glycol or phosphatidylserine. The latter was used to mimic phosphatidylserine-harboring apoptotic cells, which are substrates for efferocytosis, an essential pro-resolution function. Both formulations induced a dexamethasone-like gene expression signature in macrophages, decreased IL6 and TNFα release, increased secretion of thrombospondin 1 and increased efferocytosis activity. Phosphatidylserine-modified liposomes exhibited a faster uptake, a higher potency and a more robust phenotype induction than polyethylene glycol-modified liposomes. Fibroblast and keratinocyte cell cultures as well as a 3D skin equivalent model showed that liposomes applied locally to wounds are preferentially phagocytosed by macrophages. These findings indicate that liposomes, in particular upon shell modification with phosphatidylserine, promote dexamethasone delivery to macrophages and induce a phenotype suitable to support chronic wound healing.

糖皮质激素是公认的抗炎药，但是由于许多严重的副作用，其用于治疗慢性炎性疾病的用途受到限制。例如，角质形成细胞和成纤维细胞功能失调会导致皮肤变薄，因此禁止长期用糖皮质激素局部治疗慢性伤口。在这里，我们开发并测试了将地塞米松局部递送至主要人类巨噬细胞的脂质体制剂，以驱动适合组织修复的抗炎/促拆分表型。脂质体装有前药地塞米松磷酸酯，并用聚乙二醇或磷脂酰丝氨酸进行表面修饰。后者被用来模拟携带磷脂酰丝氨酸的凋亡细胞，这些细胞是有效胞吐作用的底物，而胞吐作用是必需的促分辨功能。两种制剂均可在巨噬细胞中诱导地塞米松样基因表达签名，降低IL6和TNFα的释放，增加分泌的地塞米松。血小板反应蛋白1和增加的胞吐活性。磷脂酰丝氨酸修饰的脂质体比聚乙二醇修饰的脂质体具有更快的吸收，更高的效能和更强的表型诱导能力。成纤维细胞和角质形成细胞的培养以及3D皮肤等效模型显示，局部应用于伤口的脂质体优先被巨噬细胞吞噬。这些发现表明脂质体，特别是在用磷脂酰丝氨酸修饰外壳时，促进地塞米松向巨噬细胞的递送并诱导适于支持慢性伤口愈合的表型。