Macrophages, as highly phenotypic plastic immune cells, play diverse roles in different pathological conditions. Changing and controlling the phenotypes of macrophages is considered a novel potential therapeutic intervention. Meanwhile, specific transmembrane proteins anchoring on the surface of the macrophage membrane are relatively conserved, supporting its functional properties, such as inflammatory chemotaxis and tumor targeting. Thus, a series of drug delivery systems related to specific macrophage membrane proteins are commonly used to treat chronic inflammatory diseases. This review summarizes macrophages-based strategies for chronic diseases, discusses the regulation of macrophage phenotypes and their polarization processes, and presents how to design and apply the site-specific targeted drug delivery systems in-vivo based on the macrophages and their derived membrane receptors, It aims to provide a better understanding of macrophages in immunoregulation and proposes macrophages-based targeted therapeutic approaches for chronic diseases.

Idiopathic pulmonary fibrosis (IPF) is serious chronic lung disease with limited therapeutic approaches. Inflammation and immune disorders are considered as the main factors in the initiation and development of pulmonary fibrosis. Inspired by the key roles of macrophages during the processes of inflammation and immune disorders, here, we report a new method for direct drug delivery into the in-situ fibrotic tissue sites in vitro and in vivo. First, liposomes containing dexamethasone (Dex-L) are prepared and designed to entry into the macrophages in the early hours, forming the macrophages loaded Dex-L delivery system (Dex-L-MV). Chemokine and cytokine factors such as IL-6, IL-10, Arg-1 are measured to show the effect of Dex-L to the various subtypes of macrophages. Next, we mimic the inflammatory and anti-inflammatory microenvironment by co-culture of polarized/inactive macrophage and fibroblast cells to show the acute inflammation response of Dex-L-MV. Further, we confirm the targeted delivery of Dex-L-MV into the inflammatory sites in vivo, and surprisingly found that injected macrophage containing Dex can reduce the level of macrophage infiltration and expression of the markers of collagen deposition during the fibrotic stage, while causing little systematic toxicity. These data demonstrated the suitability and immune regulation effect of Dex-L-MV for the anti-pulmonary process. It is envisaged that these findings are a step forward toward endogenous immune targeting systems as a tool for clinical drug delivery.