Therapeutic Inflammatory Monocyte Modulation Using Immune-Modifying Microparticles

Abstract

Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that infused negatively charged, immune-modifying microparticles (IMPs), derived from polystyrene, microdiamonds, or biodegradable poly(lactic-co-glycolic) acid, were taken up by inflammatory monocytes, in an opsonin-independent fashion, via the macrophage receptor with collagenous structure (MARCO). Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen through apoptotic cell clearance mechanisms and, ultimately, caspase-3–mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, experimental autoimmune encephalomyelitis, dextran sodium sulfate–induced colitis, thioglycollate-induced peritonitis, and lethal flavivirus encephalitis markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms, and promoted tissue repair. Together, these data highlight the intricate interplay between scavenger receptors, the spleen, and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes.

Harnessing Nanoparticles for Immune Modulation

“…NPs can be engineered to deliver, alone or in any combination, small-molecule drugs (including immune suppressants and chemotherapeutic agents), proteins (hormones and antibodies), peptides (for vaccine or immune tolerance purposes), DNA (as part of gene therapy approaches), miRNAs, and even machinery to target clustered regularly interspaced short palindromic repeat (CRISPR) components for gene-editing purposes. It is now clear that the physiochemical characteristics of unadorned NPs can also alter immune responses independently of any associated active pharmaceutical ingredient [8].…”

“…Furthermore, NPs with a charge below −30 mV have been found to have anti-inflammatory properties and when combined with antigen can induce antigen-specific immune tolerance [6,8,9]. This phenomenon is associated with the ability specifically to target scavenger receptors such as MARCO on monocytes and macrophages [6,8,9].…”

“…In vivo the formation of a protein corona has been associated with little to no impact on NP delivery and function [8]. However, proteins binding to NPs could feasibly alter NP charge or mask functional groups important for NP targeting to certain receptors and/or enhance clearance of NPs by phagocytes [27,36,40].…”

“…The latter cells are essential for the daily filtering and phagocytosis of apoptotic cells and other debris from the blood [48,55,56] and these cells are critically associated with the maintenance of peripheral tolerance. The delivery of NPs via the IV route, in the absence of adjuvant, promotes immune tolerance and provides an avenue to modulate circulating inflammatory monocytes [6,8,9].…”

“…For example, NPs may be engineered to specifically target cells of the mononuclear phagocyte system (MPS) for the purposes of restoring peripheral immune tolerance or to regulate aberrant monocyte activities during severe inflammation [2,[4][5][6][7]. Five-hundred-nanometer NPs with negative zeta potential can be harnessed to target circulating monocytes, reducing their potential for causing immune pathology in numerous experimental disease models including West Nile virus (WNV) encephalitis, myocardial infarction, and inflammatory bowel disease (IBD) [8]. The combination of such NPs with specific autoantigens can also be used to restore peripheral immune tolerance in autoimmune models including experimental autoimmune encephalitis (EAE) [5][6][7]9].…”