Engineering Strategies for Lymph Node Targeted Immune Activation

Development of vaccine technology that induces long lasting and potent adaptive immune responses is of vital importance to combat emerging pathogens and to design the next generation of cancer immunotherapies. Advanced biomaterials such as nanoparticle carriers are intensively explored to increase the efficacy and safety of vaccines and immunotherapies, based on their intrinsic potential to focus the therapeutic payload onto the relevant immune cells and to limit systemic distribution. With adaptive immune responses being primarily initiated in lymph nodes, the potency of nanoparticle vaccines in turn is tightly linked to their capacity to reach and accumulate in the lymph nodes draining the immunization site. Here, we discuss the main strategies applied to increase nanoparticle delivery to lymph nodes: (1) direct lymph node injection, (2) active cell-mediated transport through targeting of peripheral dendritic cells, and (3) exploiting passive transport through the afferent lymphatics.The intralymph nodal injection is obviously the most direct way for nanoparticles to reach lymph nodes, and multiple studies have demonstrated its capability in enhancing immunostimulant drugs' immune activation and increasing the therapeutic window. However, the requirement of using ultrasound guidance for mapping lymph nodes in patients renders intranodal administration unsuited for mass vaccination campaigns. As lymph nodes are fine structured organs with lymphocytes and chemokine gradients arrayed in a highly ordered fashion, the breakdown of such formats by the intralymph nodal injection is another concern. The exploitation of dendritic cells as live vectors for transporting nanoparticles to lymph nodes has intensively been studied both ex vivo and in vivo. While ex vivo engineering of dendritic cells in theory can achieve 100% dendritic cell-specific selectivity, a scenario impossible to be achieved in vivo, this procedure is usually laborious and complicated and entails the participation of professional staff and equipment. In addition, the poor efficiency of dendritic cell migration to the draining lymph node is another significant limitation following the injection of ex vivo cultured dendritic cells. Thus, in vivo targeting of surface receptors, particularly C-type lectin receptors, on dendritic cells by conjugating nanoparticles with antibodies or ligands is intensively studied by both academia and industry. Although such nanoparticles in vivo still face nonspecific engulfment by various phagocytes, multiple studies have shown its feasibility in targeting dendritic cells with high selectivity. Moreover, through optimizing the physicochemical properties of nanoparticles, nanoparticles can passively drain to lymph nodes carried by the interstitial flow. Compared to dendritic cell-mediated transport, passive draining is much faster and of higher efficiency. Of all such properties, size is the most important parameter as large particles (>500 nm) can only reach lymph nodes by an active cell-mediated transport. Other surface properties, such as the charge and the balance of hydrophobicity-vs-hydrophilicity, strongly influence the mobility of nanoparticles in the extracellular space. In addition, albumin, a natural fatty acid transporter, has recently been demonstrated capable of binding the amphiphiles through their lipid moiety and subsequent transporting them to lymph nodes.