A significant fraction of the total immune cells in the body are located in several hundred lymph nodes, in which lymphocyte accumulation, activation and proliferation are organized. Therefore, targeting lymph nodes provides the possibility to directly deliver drugs to lymphocytes and lymph node-resident cells and thus to modify the adaptive immune response. However, owing to the structure and anatomy of lymph nodes, as well as the distinct localization and migration of the different cell types within the lymph node, it is difficult to access specific cell populations by delivering free drugs. Materials can be used as instructive delivery vehicles to achieve accumulation of drugs in the lymph nodes and to target specific lymph node-resident cell subtypes. In this Review, we describe the compartmental architecture of lymph nodes and the cell and fluid transport mechanisms to and from lymph nodes. We discuss the different entry routes into lymph nodes and how they can be explored for 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.

Material design for lymph node drug delivery.

Lymph node targeting strategies to improve vaccination efficacy

Vaccines are the key technology to combat existing and emerging infectious diseases. However, increasing the potency, quality and durability of the vaccine response remains a challenge. As our knowledge of the immune system deepens, it becomes clear that vaccine components must be in the right place at the right time to orchestrate a potent and durable response. Material platforms, such as nanoparticles, hydrogels and microneedles, can be engineered to spatially and temporally control the interactions of vaccine components with immune cells. Materials-based vaccination strategies can augment the immune response by improving innate immune cell activation, creating local inflammatory niches, targeting lymph node delivery and controlling the time frame of vaccine delivery, with the goal of inducing enhanced memory immunity to protect against future infections. In this Review, we highlight the biological mechanisms underlying strong humoral and cell-mediated immune responses and explore materials design strategies to manipulate and control these mechanisms. The immune response to a vaccine is characterized by a complex time-dependent interplay between various cell types and molecules in different tissues in our body. This Review explores materials-based strategies for the spatial and temporal control of the mechanisms that underlie vaccine immune responses.

/pdf/designing-spatial-and-temporal-control-of-vaccine-responses-3lwnghp49g.pdf

Designing spatial and temporal control of vaccine responses

A low response rate, acquired resistance and severe side effects have limited the clinical outcomes of immune checkpoint therapy. Here, we show that combining cancer nanovaccines with an anti-PD-1 antibody (αPD-1) for immunosuppression blockade and an anti-OX40 antibody (αOX40) for effector T-cell stimulation, expansion and survival can potentiate the efficacy of melanoma therapy. Prophylactic and therapeutic combination regimens of dendritic cell-targeted mannosylated nanovaccines with αPD-1/αOX40 demonstrate a synergism that stimulates T-cell infiltration into tumours at early treatment stages. However, this treatment at the therapeutic regimen does not result in an enhanced inhibition of tumour growth compared to αPD-1/αOX40 alone and is accompanied by an increased infiltration of myeloid-derived suppressor cells in tumours. Combining the double therapy with ibrutinib, a myeloid-derived suppressor cell inhibitor, leads to a remarkable tumour remission and prolonged survival in melanoma-bearing mice. The synergy between the mannosylated nanovaccines, ibrutinib and αPD-1/αOX40 provides essential insights to devise alternative regimens to improve the efficacy of immune checkpoint modulators in solid tumours by regulating the endogenous immune response.

Immunization with mannosylated nanovaccines and inhibition of the immune-suppressing microenvironment sensitizes melanoma to immune checkpoint modulators.

Improving Vaccine and Immunotherapy Design Using Biomaterials

https://dash.harvard.edu/bitstream/handle/1/33029819/4973867.pdf?sequence=1

Targeted Delivery of Immunomodulators to Lymph Nodes

Dioscin induces M1 macrophage polarization through Connexin-43 Channels in Tumor-associated-macrophages-mediated melanoma metastasis.

Dioscin, a natural steroidal saponin isolated from traditional Chinese medicine, is re-ported to possess antitumor activity against various cancers including gastric cancer (GC). GC patients are commonly found with low expression of Connexin 43 (Cx43) and activated epithelial– mesenchymal transition (EMT). The aim of this study was to investigate the mechanism of dioscin in inhibiting the proliferation, invasion, and metastasis of GC. Cell migration was detected using wound healing analysis while the invasion was used in Transwell membrane chambers. Colony-forming assays were re-searched for cell potential capacity in proliferation. The data of 68 GC patients treated with radical gastrectomy were collected from 2017 to 2019. The clinicopathological data were recorded for retrospective analysis. Cx43 was measured by immunohistochemistry in GC tissues from patients. EMT-related proteins and PI3K/Akt pathway-associated proteins were observed by using Western blot analysis. Dioscin inhibited the proliferation, migration, and invasion of SGC-7901 cells. Dioscin increased the expression of E-cadherin but decreased the expression of N-cadherin, vimentin, and snail-1. Besides, lower-level Cx43 is expressed in GC tissues compared with adjacent normal tissues. Additionally, dioscin downregulated the levels of p-Akt, p-mTOR, and p-PI3K. This research indicated that dioscin may inhibit EMT via increasing the expression of Cx43 and suppress the phosphorylation of PI3K/Akt signaling pathway and then inhibit the proliferation, invasion, and metastasis of GC.

Connexin 43 upregulation by dioscin‐inhibited gastric cancer metastasis by suppressing
 PI3K
 /Akt pathway

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Targeted Delivery of Immunomodulators to Lymph Nodes

Dioscin induces M1 macrophage polarization through Connexin-43 Channels in Tumor-associated-macrophages-mediated melanoma metastasis.

Connexin 43 upregulation by dioscin‐inhibited gastric cancer metastasis by suppressing PI3K /Akt pathway