Immune cell-mediated drug delivery for the treatment of inflammatory diseases

Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease and cancer. Improving localised delivery of immunosuppressive drugs to inflamed tissue in a non-invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Employing immune cells for active transport of drugs and drug-loaded nanocarriers to a target site is a promising recent approach. Particularly, in the context of drug delivery for anti-inflammation therapy, immune cells have the intrinsic functions to migrate to and infiltrate the inflamed tissue. Here, a delivery strategy using neutrophils loaded with methotrexate (MTX)-liposomes ex vivo to deliver MTX to target sites was first investigated in vitro. This hybrid system efficiently migrated following an inflammatory chemokine gradient and triggered release of loaded liposomes via neutrophil extracellular traps (NETs) formation in an inflammatory environment was achieved. Subsequent re-uptake of the released liposomes by target macrophages provided detailed support for in vivo treatment studies. In parallel, macrophages were evaluated as alternative immune cells to carry nanoparticles. Given the advantage of a well-defined release mechanism (NETs formation), MTX-liposome loaded neutrophils were chosen over a macrophage-based system to be further validated in vivo using two mouse models of inflammation, a lipopolysaccharide (LPS)-injury skeletal muscle model and a myocardial ischemia reperfusion injury (IRI) model. The migratory behaviour of liposome-loaded neutrophils was confirmed by demonstrating the neutrophil-mediated delivery of liposomes to the inflamed muscle and the injured heart. A single low-dose injection of the hybrid system locally reduced inflammatory cytokine levels in the inflamed muscle and slightly improved the pumping efficiency of the IRI heart. These results highlight the advantages of immune cell-mediated drug delivery, which is a versatile strategy that allows combinations with different types of nanoparticles encapsulating various drugs to reduce tissue inflammation and actively promote repair in inflammatory diseases. Open Access