Figure 2. Characteristics of central and peripheral trained immunity and target tissues for therapeutic induction of trained immunity.

(Top Right) Central training occurs in progenitor cells of the bone marrow (shown here via Bacille Calmette-Guérin, BCG training of hematopoietic stem cells, HSCs), leading to long-lived, multi-generational training in daughter cells. Central training is also directly implicated in the pathogenesis of autoinflammatory diseases, such as atherosclerosis and diabetes. Directed targeting to the bone marrow can access hematopoietic stem cells for long-lived central training. (Left and Bottom) Peripheral trained immunity can encompass tissue-resident innate immune cells and stromal cells, such as epithelial cells and fibroblasts (shown here with small molecule training in the alveoli of the lung, Kupffer cells in the liver, and Peyer’s Patches in the small intestine). Peripheral training can provide local resistance to infection, cancer, and other inflammatory insults. A combination of passive and active targeting approaches can be used to access peripheral training in the lung, gut, and liver. Respiratory delivery can be achieved with aerosols, gastrointestinal delivery can be targeted with delayed release systems, and hepatic delivery can be achieved with intravenous delivery of nanoparticles, which naturally accumulate in the liver. This figure was created with BioRender.com.