Targeting intracellular and extracellular receptors with nano-to-macroscale biomaterials to activate immune cells.

Activation of immune cells is an essential process in innate and adaptive immunity. A high number of immune cell activation pathways have been discovered, which are stimulated via various intra- and extracellular receptors. Small-molecule and macromolecular agonists have been identified to target immune receptors in preclinical research and clinical practice. However, current immunostimulants are often associated with undesired side effects and/or low potency in vivo. These two issues have been addressed with multiscale biomaterials. In this review, we summarize and discuss the most explored intra/extracellular immune receptors which have been targeted with immunoactivating biomaterials. To target intracellular immune receptors, nano/microscale materials have been employed to deliver agonists into the endo/lysosomes or the cytoplasm. To target surface immune receptors, nano-to-macroscale biomaterials have been engineered to engage with them to activate immune cells. In this context, biomaterials are not only the drug carriers, but also function as part of the immunostimulants. The biomaterials-based modalities have shown clearly enhanced immunoactivation potency and decreased side effects compared to native immunostimulants. It is envisaged that nano-to-macroscale biomaterials will greatly contribute to the development of more effective strategies for immunoactivation, which have the potential to reshape future vaccination and immunotherapy.