Innovations in lymph node targeting nanocarriers

Abstract

Lymph nodes are secondary lymphoid tissues in the body that facilitate the co-mingling of immune cells to enable and regulate the adaptive immune response. They are also tissues implicated in a variety of diseases, including but not limited to malignancy. The ability to access lymph nodes is thus attractive for a variety of therapeutic and diagnostic applications. As nanotechnologies are now well established for their potential in translational biomedical applications, their high relevance to applications that involve lymph nodes is highlighted. Herein, established paradigms of nanocarrier design to enable delivery to lymph nodes are discussed, considering the unique lymph node tissue structure as well as lymphatic system physiology. The influence of delivery mechanism on how nanocarrier systems distribute to different compartments and cells that reside within lymph nodes is also elaborated. Finally, current advanced nanoparticle technologies that have been developed to enable lymph node delivery are discussed.

Keywords: Controlled release; Lymph node drug delivery; Nanoparticle; Nanotechnology; Targeted delivery.

Figure 1.. Schematic diagram depicting transport mechanisms and barriers in the tissue interstitium, lymphatic vasculature, and lymph nodes.

Small molecules and NPs in tissue interstitium can be transported to the SCS of lymph nodes via size-exclusive passive transport and lymph homing cells in interstitial flow. Small molecules lower than 70 kDa can access to lymph node parenchyma via lymph node conduits.

Figure 2.. Extent, timing, and spatial distribution of delivery to the lymph node are influenced by mechanism of transport and lymph node structural barriers.

(A) Size-varied fluorescent tracer system facilitates (B) study of transport mechanisms to the lymph node. (C–E) Spatial distribution of each tracer within the lymph node 4 and 72 h post-intradermal administration. (C) Representative draining lymph node images, (D) Quantification of penetration depth into the lymph node for each tracer 4 and 72 h post-administration, (E) Average distance of tracer from lymph node capsule. (F) Extent of delivery of each tracer to cells within lymph node measured by frequency of association through flow cytometry. (G) Spatial distribution of leukocyte subsets within lymph node structure. (H) Quantity of each marker-positive cell type within CD45⁺ cells that is tracer positive 4, 24, and 72 h post-administration, as measured by flow cytometry. Scale bars, 200 um; * indicates significance by two-way analysis of variance (ANOVA) (D–F) or one-way ANOVA (H) with Tukey’s comparison (* indicates P < 0.05, *** indicates P < 0.005, **** indicates P < 0.001). n = 5 to 8 mice. Figures adapted and modified with permission from [117,131].

Figure 3.. Schematic diagram depicting strategies of advanced NPs rationally engineered for delivery to lymph nodes.

(A) Proteins are engineered to efficiently transport to lymph nodes via size-dependent lymph drainage. (B) Trojan horse NPs efficiently transport into lymph due to their optimal size for lymphatic uptake and then achieve efficient release of small molecular cargos into the lymph node parenchyma using release from the carrier into lymph. (C) Cargos loaded in PNAd-targeting ADCs and NPs are transported to the lymph node after uptake by the HEVs after administration into the systemic circulation. (D) Magnetic NPs efficiently transport to lymph nodes when external magnetic is applied near the targeted lymph nodes. (E) NPs camouflaged with lymph-homing leukocyte cell membranes accumulate within lymph nodes due to both their optimal size for uptake into lymph and NP surface-coating chemokines, L-selectin, and integrins.