Mesenchymal Stem Cell-Derived Extracellular Vesicles as Idiopathic Pulmonary Fibrosis Microenvironment Targeted Delivery

Abstract

Idiopathic pulmonary fibrosis (IPF) affects an increasing number of people globally, yet treatment options remain limited. At present, conventional treatments depending on drug therapy do not show an ideal effect in reversing the lung damage or extending the lives of IPF patients. In recent years, more and more attention has focused on extracellular vesicles (EVs) which show extraordinary therapeutic effects in inflammation, fibrosis disease, and tissue damage repair in many kinds of disease therapy. More importantly, EVs can be modified or used as a drug or cytokine delivery tool, targeting injury sites to enhance treatment efficiency. In light of this, the treatment strategy of mesenchymal stem cell-extracellular vesicles (MSC-EVs) targeting the pulmonary microenvironment for IPF provides a new idea for the treatment of IPF. In this review, we summarized the inflammation, immune dysregulation, and extracellular matrix microenvironment (ECM) disorders in the IPF microenvironment in order to reveal the treatment strategy of MSC-EVs targeting the pulmonary microenvironment for IPF.

Keywords: bioengineering; extracellular vesicles; idiopathic pulmonary fibrosis; mesenchymal stem cells; microenvironment; targeted delivery.

Figure 1

Secretion and uptake of extracellular vesicles (EVs). EVs are currently classified into three categories depending on their origin, secretion mechanism, and size: exosomes, microvesicles, and apoptotic bodies. EVs interact with recipient/target cells and act as messengers for signal delivery: interactions with plasma membrane receptors, phagocytosis into cells, and direct fusion with the plasma membrane.

Figure 2

The dyshomeostasis of the microenvironment in idiopathic pulmonary fibrosis (IPF). In individuals with IPF, lung epithelial injury leads to the production of inflammatory factors, profibrotic cytokines, and chemokines secreted by alveolar macrophages. This results in activation of fibroblasts and differentiation into myofibroblasts, which produces extracellular matrix (ECM), leading to thickening of the lung interstitium. In IPF, the microenvironment altered the Th1/Th2 balance in the lung. IFN-γ produced by Th1 cells inhibits fibrocyte differentiation and promotes M1 macrophage formation. IL-17 production by Th17 cells in the lung also promotes fibroblast activation. The imbalance between Th17 and Tregs can affect pulmonary fibrosis.

Figure 3

Overview of therapeutic modalities of MSC-EVs for IPF. Administration routes in EVs-based strategies applicable in IPF. MSC-EVs loading techniques to produce target and effective EVs-based nanotherapeutics.