Abstract
Many cells possess the ability to engulf and incorporate particles by phagocytosis. This active process is characteristic of microorganisms as well as higher order species. In mammals, monocytes, macrophages, and microglia are among the so-called professional phagocytes. In addition, cells such as fibroblast and chondrocytes are classified as nonprofessional phagocytes. Professional phagocytes play important roles in both the innate and adaptive immune responses, wound healing, and tissue homeostasis. Consequently, these cells are increasingly studied as targets and vectors of therapeutic intervention to treat a range of diseases. Professional phagocytes are notoriously difficult to transfect limiting their study and manipulation. Consequently, efforts have shifted towards the development of nanoparticles to deliver a cargo to phagocytic cells via phagocytosis. However, this approach carries significant technical challenges, particularly for protein cargos. We have focused on the development of nanoscale cocrystalline protein depots, known as PODS®, that contain protein cargos, including cytokines. Here, we show that PODS are readily phagocytosed by nonprofessional as well as professional phagocytic cells and have attributes, such as highly sustained release of cargo, that suggest potential utility for the study and exploitation of phagocytic cells for drug delivery. Monocytes and macrophages that ingest PODS retain normal characteristics including a robust chemotactic response. Moreover, the PODS-cytokine cargo is secreted by the loaded cell at a level sufficient to modulate the behavior of surrounding nonphagocytic cells. The results presented here demonstrate the potential of PODS nanoparticles as a novel molecular tool for the study and manipulation of phagocytic cells and for the development of Trojan horse immunotherapy strategies to treat cancer and other diseases.
Highlights
Phagocytic cells engulf microscopic particles through an active process [1] and are classified as professional or nonprofessional with the latter taking up a more limited range of materials
Our findings demonstrate the utility of PODS for macrophage-based research and suggest their potential utility in Trojan horse drug delivery strategies to treat cancer and other diseases
We first tested our expectation that PODS crystals can be phagocytosed by primary murine monocytes and macrophages
Summary
Phagocytic cells engulf microscopic particles through an active process [1] and are classified as professional or nonprofessional with the latter taking up a more limited range of materials. Professional phagocytes include monocytes, macrophages, microglia, dendritic cells, and neutrophils. Nonprofessional phagocytes include chondrocytes, fibroblasts, erythrocytes, and epithelial cells. Macrophages contribute to the innate and adaptive immune response. They help to heal wounds and regulate tissue homeostasis [2]. Macrophages display phenotypic plasticity and can be polarized by microenvironmental cues to a spectrum of phenotypes very broadly characterized by the classically activated proinflammatory M1 phenotype and the alternatively activated anti-inflammatory M2 phenotype. Macrophages are able to switch between these different phenotypes depending on changing requirements [3]
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