Macrophages are immune cells involved in both innate and adaptive immunity. They digest pathogens and dead cells, as well as activate other immune cells. Macrophages are good carriers of macromolecules and small-molecule drugs. These cells can be utilized to deliver drugs by loading drugs or drug-loaded nanoparticles into macrophages, macrophage membranes, and macrophage-derived vesicles. Macrophage-mediated drugs can potentially overcome the drawbacks of common carrier materials, which are low biocompatibility, short circulation time, and undesirable immunogenicity.

 

Macrophage drug delivery has been proven to have longer circulation time, higher stability, lower immunogenicity, slower drug release, and improved drug targeting. Macrophage also shows biocompatibility and versatility. Drugs can be inserted through direct loading into macrophages, encapsulation with macrophage membranes, or encapsulation with macrophage-derived vesicles. So far, macrophage has been demonstrated to treat inflammation, tumor, HIV, Parkinson’s, atherosclerosis, and intracellular parasites.

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Advantages of Macrophage as Drug Dispatcher

• Prolonged circulation time: Macrophages are one of the mononuclear phagocyte cells, thus macrophage-mediated drugs are recognized as self immunity by the host and will not be phagocytized by other immune cells. As the drug stays longer inside the body, drug intake frequency can be reduced.

• Biocompatibility: Macrophage doesn’t cause toxicity inside the body, doesn’t affect blood biochemistry, and can be metabolized into non-toxic substances.

• Improved stability and minimized immunogenicity: Macrophage can protect drugs from premature inactivation or degradation and doesn’t trigger immune responses.

• Sustained drug release: Macrophage cell membranes are semipermeable, resulting in slower drug release and reduce fluctuations in the blood.

• Improved drug targeting: As immune cells, macrophages flock at inflammatory sites. Therefore, they also carry the drugs inside them to specific targets which reduces side effects.

• Varied substances delivery: Macrophage can deliver a wide variety of substances such as poly nanoparticles, liposomes, nanozymes, and natural drugs.

 

Drug-Loading Methods

Direct Loading

• Incubation: Incubation of macrophages with drugs or drug-loaded NPs under appropriate culture conditions, then the macrophages phagocytose the drugs.

• Adhesion: The use of a cellular backpack which is a thin film prepared via a layer-by-layer spray deposition technique that can ride on macrophage surfaces without affecting cell functions or getting internalized. 

• Low Permeability Resealing: Target-specific delivery systems limit the in vivo degradation of antioxidant enzymes. By imitating the intestinal barrier, these models are useful tools for permeability screening purposes and are useful to examine the permeability of less soluble drugs

• Electroporation: The usage of short high-voltage pulses to overcome the barrier of the cell membrane. This can increase drug loading without requiring cells to phagocytose it.

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Encapsulation

• Within macrophage membranes: Extraction of macrophage membrane requires processes of destruction and centrifugation to get rid of cell contents, as well as the addition of inhibitors to prevent membrane degradation. Membranes are wrapped onto drugs or drug-loaded NPs by ultrasonication or mechanical extrusions.

• Inside macrophage-derived vesicles: Macrophages are cultured and stimulated using a particular substance to secrete vesicles. These vesicles are known to have membrane proteins similar to macrophage membrane proteins.

 

Applications of Macrophage-Mediated Drug Delivery

Anti-Inflammatory Treatment

• Drug-loaded macrophages can still bind endotoxins and cytokines, just like the original macrophages.

• A research performed on a mouse has shown that tacrolimus-loaded NPs inserted inside a macrophage-derived microvesicle has increased the anti-inflammatory effect of tacrolimus and significantly inhibited arthritis.

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Anti-Tumor Therapy

• Macrophage is divided into two phenotypes, M1 and M2. M1 macrophages produce cytokine in the tumor microenvironment, giving signals to more immune cells to promote immune response towards tumor cells. Meanwhile, M2 macrophages promote the growth of tumor cells. Research has demonstrated that treating macrophages with an inhibitor can polarize M2 macrophages into M1 macrophages.

• Macrophage loaded with doxorubicin has been proven to inhibit the growth and propagation of breast cancer cells in mice.

• Materials with good photothermal conversion ability have high efficiency in converting light radiation into heat energy. Transporting these materials by encapsulating them with macrophage membranes results in good photothermal ability, biocompatibility, ability to avoid immune response and precise tumor targeting.

• More effective tumor targeting by NPs-loaded vesicles will improve the possibility of tumor imaging

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Anti-HIV Therapy

Bone marrow-derived macrophages (BMMs) were developed to be used as carriers of nanoparticle indinavir (NP-IDV) formulation. Indinavir (IDV) is a protease inhibitor used as a component of HIV treatment therapy. It is soluble white powder administered orally in combination with other antiviral drugs. The drug prevents protease from functioning normally. 

 

Treatment of Other Diseases 

• Parkinson's disease: A research performed on mice has shown that macrophages significantly reduce the neuroinflammation and degeneration of substantia nigra. Progressive loss of dopaminergic neurons in the substantia nigra is a trait of Parkinson’s disease, thus macrophages can achieve active targeting of Parkinson’s therapy.

• Atherosclerosis: A study has shown that NPs-loaded macrophages targeting the endothelial cells have successfully eliminated more than 90% of reactive oxygen species. Transportation to lesion sites was improved and pro-inflammatory substances were scavenged.

• Intracellular parasites: Vesicles loaded with Amphotericin B reduce the drug’s toxicity while still the same therapeutic effect can be achieved either with a higher or lower dose.

• Bacterial recognition: Macrophages can be co-cultured with bacteria to increase the expression of recognition receptors.

 

Additional Readings: 

Peng, R. et al., 2020. ‘Macrophage-Based Therapies for Atherosclerosis Management’. Journal of Immunology Research. 2020. Available at: https://www.hindawi.com/journals/jir/2020/8131754/

 

Tacke, F. 2017. ‘Targeting hepatic macrophages to treat liver diseases’. Journal of Hepatology. 66(6). Available at: https://www.journal-of-hepatology.eu/article/S0168-8278(17)30125-3/fulltext

 

Noy, R. and Pollard, J. W. 2014. ‘Tumor-Associated Macrophages: From Mechanisms to Therapy’. Immunity. 41(1). Available at: https://www.sciencedirect.com/science/article/pii/S1074761314002301