Figure 6.

Use of nanosized drug delivery systems (DDSs) to fight tuberculosis. (A) Nanosized DDSs can be used to track Mycobacterium tuberculosis (Mtb) not only in the lungs (the site of infection in most clinical cases) but also in cases of extra-pulmonary tuberculosis, reaching organs such as the bones, brain, eyes, liver, kidneys or spleen. Therefore, DDSs can be administered intravenously, orally or pulmonary, with the latter being of particular interest. (B) Trachea and bronchioles constitute the first barrier for the nanosized DDSs during pulmonary administration. Exogenous particles such as NPs can be removed by means of mucociliary clearance, where the periciliary and mucus layers play a crucial role. The Mtb biofilm is another obstacle for drug nanocarriers. (C) If DDSs overcome the previous barriers, they will later face the clearance mechanisms in the alveoli. In these cavities, DDSs are at the mercy of pulmonary surfactant and the host’s immune defenses. Alveolar macrophages and dendritic cells readily uptake NPs. (D) Granulomas are formed in the lungs in order to contain the Mtb infection, and are another biological barrier for NPs. (E) Targeting alveolar macrophages with NPs is an attractive strategy. Whereas free drugs often poorly penetrate inside infected macrophages, nanocarriers can act as “Trojan horses” to carry drugs inside the cells. Nanocarriers can also be coated with ligands such as mannose for active targeting. (F) DDSs are engineered to overcome multiple barriers in the body and achieve drug delivery at Mtb locations. Drugs are (co-)encapsulated in the NPs’ cores, whereas coatings can modulate the interactions with the biological medium. Created with BioRender.com.