2) because these cells are more sensitive to phagocytosing large particulate materials than small molecules. drug delivery, including the lymphatics, blood capillaries, high endothelial venules, cell-mediated pathways, homing of circulating lymphocytes and direct lymph node injection. We examine different nanoscale and microscale materials for the targeting of specific immune cells and highlight their potential for the treatment of immune dysfunction and for cancer immunotherapy. Finally, we give an outlook to the field, exploring how lymph node targeting can be improved by the use of materials. Lymph nodes are essential tissues of the immune system, providing a structure to gather immunogenic information from peripheral tissues1. Lymph nodes are one of the primary organs in which the adaptive immune response of the body occurs, and, therefore, their health is usually important for maintaining a functioning immune GLUT4 activator 1 system2C4. The lymph nodes in the body are connected immunologically speaking by migrating lymphocytes, which enter the lymph node to find their cognate antigen and then re-enter the circulation to provide protective immunity Prkwnk1 in the periphery. Thus, delivering drugs directly to lymph nodes provides an opportunity to address a variety of local GLUT4 activator 1 and systemic immunological challenges, as well as diseases that afflict cells of the immune system or are regulated by the adaptive immune system. The efficacy of an administered drug is determined by the therapeutically relevant drug bioavailability and the duration of action at the target site. Deleterious off-target effects and toxicities reduce the maximum tolerable dose, requiring either alterations to the route of administration or advanced formulations to improve the specificity of tissue and cell delivery. Biomaterials- based delivery systems can be applied to address these challenges owing to the potential of materials to prolong circulation times of intravenously infused agents or their retention after administration in peripheral tissues, to leverage specific physiological structures and pathways to improve tissue targeting or clearance pathways and to target specific cells within tissues. Therefore, drug carriers, such as polymers, lipids and inorganic materials, can alter the pharmacokinetics and biodistribution of their associated small molecule drug. A variety of materials are being explored for lymph node drug delivery, including synthetic micelles5C10, dendrimers11,12, inorganic nanoparticles13,14 and liposomes15,16. Each of these materials has advantages for specific applications and/or targets; however, GLUT4 activator 1 in general, drug carriers improve lymph node targeting by increasing the molecular weight of the drug, which favourably affects lymphatic uptake, by reducing vasculature permeability to improve lymphatic drainage, by targeting phagocytic cells in peripheral tissues to facilitate transport GLUT4 activator 1 to the lymph nodes or through a combination of these effects. Various physiochemical properties of materials can be tailored to target the lymph nodes for drug delivery17 and for lymph node imaging18. In this Review, we discuss materials that are designed to target specific cells within the lymph node. We examine lymph nodes and their specific cell subtypes as valuable immunotherapeutic and drug targets, investigate the mechanisms of endogenous molecular and cellular transport to and within the lymph nodes and highlight the use of bioinspired systems and materials for basic immunology studies and as drug delivery systems exploiting these pathways. Targeting lymph nodes One of the most obvious rationales for targeting lymph nodes is in the context of vaccination, which is generally used to generate adaptive immunity but also to induce immune tolerance. For vaccination, antigens are often delivered in conjunction with co-stimulatory agents that induce immunity or with immunosuppressive and/or tolerogenic agents that induce tolerance signals in antigen-presenting cells (APCs), which take up and process antigens for presentation to lymphocytes. APCs comprise a diverse.