Neutrophils Enable Local and Non‐Invasive Liposome Delivery to Inflamed Skeletal Muscle and Ischemic Heart

Abstract

hampered by poor bioavailability and biostability, [3] undesirable off-target effects, [4] and obstacles presented by biological barriers, [5] thus motivating the development of drug delivery systems for efficient and localized delivery to affected tissue. Nanoparticle-based drug delivery systems for the treatment of inflammation are a powerful tool to target anti-inflammatory drugs to inflamed tissues. However, efficient local delivery remains challenging. Main hurdles include sequestration of nanoparticles by phagocytic cells and biological barriers such as the endothelium hindering infiltration and accumulation in the inflamed tissue. [6,7] Employing immune cells for active transport of drugs and drug-loaded nanocarriers to a target site is a promising recent approach. [8-10] Neutrophils are one of the most abundant, and also one of the first leukocytes to reach inflammatory tissue. [11,12] Upon activation, neutrophils can form neutrophil extracellular traps (NETs) within a few hours, a defined release mechanism that enables neutrophils to serve as a delivery system for drugs or loaded nanocarriers at early stages of inflammation. [13] These properties of neutrophils have recently been leveraged to deliver paclitaxel-loaded liposomes to suppress postoperative glioma recurrence. [8] Another study designed nanocarriers to attach to neutrophils and monocytes in circulation that subsequently Uncontrolled inflammation is a major pathological factor underlying a range of diseases including autoimmune conditions, cardiovascular disease, and cancer. Improving localized delivery of immunosuppressive drugs to inflamed tissue in a non-invasive manner offers significant promise to reduce severe side effects caused by systemic administration. Here, a neutrophil-mediated delivery system able to transport drug-loaded nanocarriers to inflamed tissue by exploiting the inherent ability of neutrophils to migrate to inflammatory tissue is reported. This hybrid system (neutrophils loaded with liposomes ex vivo) efficiently migrates in vitro following an inflammatory chemokine gradient. Furthermore, the triggered release of loaded liposomes and reuptake by target macrophages is studied. The migratory behavior of liposome-loaded neutrophils is confirmed in vivo by demonstrating the delivery of drugloaded liposomes to an inflamed skeletal muscle in mice. A single low-dose injection of the hybrid system locally reduces inflammatory cytokine levels. Biodistribution of liposome-loaded neutrophils in a human-disease-relevant myocardial ischemia reperfusion injury mouse model after i.v. injection confirms the ability of injected neutrophils to carry loaded liposomes to inflammation sites. This strategy shows the potential of nanocarrier-loaded neutrophils as a universal platform to deliver anti-inflammatory drugs to promote tissue regeneration in inflammatory diseases.

Recent progress in targeted delivery vectors based on biomimetic nanoparticles

“…The nanoparticles neutralized proinflammatory cytokines, suppressed synovial inflammation, and alleviated joint damage in inflammatory arthritis via dampening the inflammation cascade. In one recent study, methotrexate (MTX)-loaded cationic liposome was encapsulated in neutrophil without removal of endocyte (MTX-liposome/neutrophils) for targeted delivery to inflammatory sites 92 . The oriented accumulation of MTX-liposome/neutrophils was demonstrated in both inflamed skeletal muscle and myocardial ischemia–reperfusion injury mice model, exhibiting the potential to regenerate inflamed tissue.…”

Non-Viral Gene Delivery Systems for Treatment of Myocardial Infarction: Targeting Strategies and Cardiac Cell Modulation

“…Circulating cells such as red blood cells, stem cells, and leukocytes were recently leveraged for drug delivery due to their long circulation times and tissue-homing properties in vivo [ 108 , 109 ]. A recent study by Molly M. Stevens group showed that neutrophils loaded with liposomes ex vivo could transport nanoparticles to inflamed skeletal muscle and ischemic hearts in mice, demonstrating neutrophils to be suitable carriers of nanoparticles to target an injured heart due to their inherent homing to inflammatory tissue [ 110 ]. To target migrating monocytes in circulation to mediate cardiac targeting of nanoparticles, Patrick C. H. Hsieh’s group developed a platelet-like proteoliposome (PLP) in which liposomes were incorporated with proteins isolated from platelets [ 111 ].…”

3D Printed Integrated Multi-Layer Microfluidic Chips for Ultra-High Volumetric Throughput Nanoliposome Preparation

“…Liposomes are spherical vesicles consisting of one or more phospholipid bilayers, can remarkably improve the permeability of encapsulated cargo within the target tissue, and have been widely employed for biomedical applications, such as nanomedicines and contrast agent ( Ringgaard et al, 2020 ; Che et al, 2020 ; Kim et al, 2019 ; Liu et al, 2017 ; Chen et al, 2017 ). Owing to their ideal size and excellent biocompatibility, liposomes are the promising carrier for a variety of agents, including drugs, small interference RNA (siRNA), plasmid DNA, etc.…”