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Key Points The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune defence, and influences a diverse range of diseases, including infection, inflammatory and metabolic diseases, and cancer. Targeted delivery to the lymphatics and lymphoid tissues has the potential to improve oral bioavailability, enhance vaccination and tolerance induction, target delivery to lymph-resident cancer metastasis and infection, and promote the utility of treatments for diseases ranging from infections such as HIV to cancer and inflammatory and metabolic disease. Selective delivery to the lymph is largely dictated by size, as macromolecules or particulate carriers are excluded from access to blood capillaries, whereas interstitial fluid flow sweeps larger constructs into the more permeable lymphatics. Lymphatic targeting may be achieved via the delivery of macromolecular therapeutics (for example, proteins and peptides), small-molecule therapeutics in association with macromolecular carriers (for example, nanoparticles, polymers, liposomes and dendrimers) or small-molecule therapeutics that associate, in situ , with endogenous macromolecular constructs (for example, lipoproteins and proteins) or cells that are transported from interstitial tissues via lymphatic rather than blood capillaries. The design of lymphatic delivery systems ranges from simple systems that rely on passive lymphatic access to more complex structures that integrate into endogenous lymph transport processes. Recent studies have suggested the presence of active transport processes that facilitate entry across the lymphatic endothelium, and delivery systems that harness these processes are emerging. In many cases, disease progression results in lymphatic remodelling. Next-generation lymphatic targeting approaches will probably seek to harness a better understanding of changes to lymphatic structure and function in disease to promote targeting to the lymphatics and enhance therapeutic utility. Future efforts in lymphatic drug delivery might usefully address barriers to the clinical translation of lymphotropic delivery vehicles, such as the lack of well-validated models to predict lymphatic uptake in humans. Targeted delivery to the lymphatic system has the potential to improve bioavailability, enhance prophylactic and therapeutic vaccination or tolerance induction, and target drug delivery to lymph-resident infection or metastasis. In this Review, Trevaskis, Kaminskas and Porter provide an overview of lymphatic targeting and delivery strategies in drug development, and discuss the clinical applications of these approaches. The lymphatic system serves an integral role in fluid homeostasis, lipid metabolism and immune control. In cancer, the lymph nodes that drain solid tumours are a primary site of metastasis, and recent studies have suggested intrinsic links between lymphatic function, lipid deposition, obesity and atherosclerosis. Advances in the current understanding of the role of the lymphatics in pathological change and immunity have driven the recognition that lymph-targeted delivery has the potential to transform disease treatment and vaccination. In addition, the design of lymphatic delivery systems has progressed from simple systems that rely on passive lymphatic access to sophisticated structures that use nanotechnology to mimic endogenous macromolecules and lipid conjugates that 'hitchhike' onto lipid transport processes. Here, we briefly summarize the lymphatic system in health and disease and the varying mechanisms of lymphatic entry and transport, as well as discussing examples of lymphatic delivery that have enhanced therapeutic utility. We also outline future challenges to effective lymph-directed therapy.

Lymphatic filariasis is a disease of considerable socioeconomic burden in the tropics. Presently used antifilarial drugs are able to strongly reduce transmission and will thus ultimately lower the burden of morbidity associated with the infection, however, a chemotherapeutic principle that directly induces a halt or improvement in the progression of the morbidity in already infected individuals would constitute a major lead. In search of such a more-effective drug to complement the existing ones, in an area endemic for bancroftian filariasis in Ghana, 33 microfilaremic and 18 lymphedema patients took part in a double-blind, placebo-controlled trial of a 6-wk regimen of 200 mg/day doxycycline. Four months after doxycycline treatment, all patients received 150-200 microg/kg ivermectin and 400 mg albendazole. Patients were monitored for Wolbachia and microfilaria loads, antigenemia, filarial dance sign (FDS), dilation of supratesticular lymphatic vessels, and plasma levels of lymphangiogenic factors (vascular endothelial growth factor-C [VEGF-C] and soluble vascular endothelial growth factor receptor-3 [(s)VEGFR-3]). Lymphedema patients were additionally monitored for stage (grade) of lymphedema and the circumferences of affected legs. Wolbachia load, microfilaremia, antigenemia, and frequency of FDS were significantly reduced in microfilaremic patients up to 24 mo in the doxycycline group compared to the placebo group. The mean dilation of supratesticular lymphatic vessels in doxycycline-treated patients was reduced significantly at 24 mo, whereas there was no improvement in the placebo group. Preceding clinical improvement, at 12 mo, the mean plasma levels of VEGF-C and sVEGFR-3 decreased significantly in the doxycycline-treated patients to a level close to that of endemic normal values, whereas there was no significant reduction in the placebo patients. The extent of disease in lymphedema patients significantly improved following doxycycline, with the mean stage of lymphedema in the doxycycline-treated patients being significantly lower compared to placebo patients 12 mo after treatment. The reduction in the stages manifested as better skin texture, a reduction of deep folds, and fewer deep skin folds. In conclusion, a 6-wk regimen of antifilarial treatment with doxycycline against W. bancrofti showed a strong macrofilaricidal activity and reduction in plasma levels of VEGF-C/sVEGFR-3, the latter being associated with amelioration of supratesticular dilated lymphatic vessels and with an improvement of pathology in lymphatic filariasis patients.

Tumor cells frequently disseminate through the lymphatic system during metastatic spread of breast cancer and many other types of cancer. Yet it is not clear how tumor cells make their way into the lymphatic system and how they choose between lymphatic and blood vessels for migration. Here we report that mammary tumor cells undergoing epithelial–mesenchymal transition (EMT) in response to transforming growth factor-β (TGF-β1) become activated for targeted migration through the lymphatic system, similar to dendritic cells (DCs) during inflammation. EMT cells preferentially migrated toward lymphatic vessels compared with blood vessels, both in vivo and in 3D cultures. A mechanism of this targeted migration was traced to the capacity of TGF-β1 to promote CCR7/CCL21-mediated crosstalk between tumor cells and lymphatic endothelial cells. On one hand, TGF-β1 promoted CCR7 expression in EMT cells through p38 MAP kinase-mediated activation of the JunB transcription factor. Blockade of CCR7, or treatment with a p38 MAP kinase inhibitor, reduced lymphatic dissemination of EMT cells in syngeneic mice. On the other hand, TGF-β1 promoted CCL21 expression in lymphatic endothelial cells. CCL21 acted in a paracrine fashion to mediate chemotactic migration of EMT cells toward lymphatic endothelial cells. The results identify TGF-β1-induced EMT as a mechanism, which activates tumor cells for targeted, DC-like migration through the lymphatic system. Furthermore, it suggests that p38 MAP kinase inhibition may be a useful strategy to inhibit EMT and lymphogenic spread of tumor cells.

Background Many studies have indicated that a history of depression increases the risk of developing Alzheimer’s disease (AD); however, the potential pathogenestic mechanism by which depression functions as a high risk factor for AD remains unknown. Recently, a “cerebral lymphatic system” referred to as “glymphatic system” has been demonstrated to be responsible for neuronal extracellular waste protein clearance via a paravascular pathway. However, the function of glymphatic pathway has not been determined in depressive disorders. Methods The present study used an animal model of chronic unpredictable mild stress (CUMS) to determine the function of glymphatic pathway by using fluorescence tracers. Immunohistochemistry was used to assess the accumulation of endogenous mouse and exogenous human amyloid beta 42 (Aβ42) in CUMS-treated mice with or without treatment with antidepressant fluoxetine. Findings Glymphatic pathway circulation was impaired in mice treated with CUMS; moreover, glymphatic pathway dysfunction suppressed Aβ42 metabolism, because the accumulation of endogenous and exogenous Aβ42 was increased in the brains of the CUMS-treated mice. However, treatment with fluoxetine reversed these destructive effects of CUMS on glymphatic system. In anhedonic mice, the expression of the water channel aquaporin 4 (AQP4), a factor in glymphatic pathway dysfunction, was down-regulated in cortex and hippocampus. Conclusion The dysfunction of glymphatic system suggested why a history of depression may be a strong risk factor for AD in anhedonic mice. We hope our study will contribute to an understanding of the risk mechanism of depressive disorder in the development of AD and the mechanisms of antidepressant therapies in AD.

Immunotherapies have been established as safe and efficient modalities for numerous tumor treatments. The lymphatic system, which is an important system, can modulate the immune system via a complex network, which includes lymph nodes, vessels, and lymphocytes. With the deepening understanding of tumor immunology, a plethora of immunotherapies, which include vaccines, photothermal therapy, and photodynamic therapy, have been established for antitumor treatments. However, the deleterious off-target effects and nonspecific targeting of therapeutic agents result in low efficacy of immunotherapy. Fortunately, nanoparticle-based approaches for targeting the lymphatic system afford a unique opportunity to manufacture drugs that can simultaneously tackle both aspects, thereby improving tumor treatments. Over the past decades, great strides have been made in the development of DC vaccines and nanomedicine as antitumor treatments in the field of lymphatic therapeutics and diagnosis. In this review, we summarize the current strategies through which nanoparticle technology has been designed to target the lymphatic system and describe applications of lymphatic imaging for the diagnosis and image-guided surgery of tumor metastasis. Moreover, improvements in the tumor specificity of nanovaccines and medicines, which have been realized through targeting or stimulating the lymphatic system, can provide amplified antitumor immune responses and reduce side effects, thereby promoting the paradigm of antitumor treatment into the clinic to benefit patients.

Reducing the first-pass hepatic effect via intestinal lymphatic transport is an effective way to increase the oral absorption of drugs. 2-Monoacylglycerol (2-MAG) as a primary digestive product of dietary lipids triglyceride, can be assembled in chylomicrons and then transported from the intestine into the lymphatic system. Herein, we propose a biomimetic strategy and report a 2-MAG mimetic nanocarrier to target the intestinal lymphatic system via the lipid absorption pathway and improve oral bioavailability. The 2-MAG mimetic liposomes were designed by covalently bonding serinol (SER) on the surface of liposomes named SER-LPs to simulate the structure of 2-MAG. Dihydroartemisinin (DHA) was chosen as the model drug because of its disadvantages such as poor solubility and high first-pass effect. The endocytosis and exocytosis mechanisms were investigated in Caco-2 cells and Caco-2 cell monolayers. The capacity of intestinal lymphatic transport was evaluated by ex vivo biodistribution and in vivo pharmacokinetic experiments. DHA loaded SER-LPs (SER-LPs-DHA) had a particle size of 70 nm and a desirable entrapment efficiency of 93%. SER-LPs showed sustained release for DHA in the simulated gastrointestinal environment. In vitro cell studies demonstrated that the cellular uptake of SER-LPs primarily relied on the caveolae- rather than clathrin-mediated endocytosis pathway and preferred to integrate into the chylomicron assembly process through the endoplasmic reticulum/Golgi apparatus route. After oral administration, SER-LPs efficiently promoted drug accumulation in mesenteric lymphatic nodes. The oral bioavailability of DHA from SER-LPs was 10.40-fold and 1.17-fold larger than that of free DHA and unmodified liposomes at the same dose, respectively. SER-LPs improved oral bioavailability through efficient intestinal lymphatic transport. These findings of the current study provide a good alternative strategy for oral delivery of drugs with high first-pass hepatic metabolism.

The pulmonary lymphatic system has emerged as a critical regulator of lung homeostasis and a key contributor to the pathogenesis of respiratory diseases. As the primary conduit responsible for maintaining fluid balance and facilitating immune cell trafficking, the integrity of lymphatic vessels is essential for preserving normal pulmonary structure and function. Lymphatic abnormalities manifest across a broad spectrum of pulmonary disorders, underscoring their significance in respiratory health and disease. This review provides an overview of pulmonary lymphatic biology and delves into the involvement of lymphatics in four major lung diseases: chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), asthma, and lung transplant rejection. We examine how lymphatic abnormalities manifest in each of these conditions and investigate the mechanisms through which lymphatic remodeling and dysfunction contribute to disease progression. Furthermore, we explore the therapeutic potential of targeting the lymphatic system to ameliorate these debilitating respiratory conditions. Despite the current knowledge, several crucial questions remain unanswered, such as the spatial and temporal dynamics of lymphatic changes, the molecular crosstalk between lymphatics and the lung microenvironment, and the distinction between protective versus detrimental lymphatic phenotypes. Unraveling these mysteries holds the promise of identifying novel molecular regulators, characterizing lymphatic endothelial phenotypes, and uncovering bioactive mediators. By harnessing this knowledge, we can pave the way for the development of innovative disease-modifying therapies targeting the lymphatic highway in lung disorders.

The aims of this study were to prepare a baicalein self-microemulsion with baicalein-phospholipid complex as the intermediate (BAPC-SMEDDS) and to compare its effects with those of conventional baicalein self-microemulsion (CBA-SMEDDS) on baicalein oral absorption and lymphatic transport. Two SMEDDS were characterized by emulsifying efficiency, droplet size, zeta potential, cloud point, dilution stability, physical stability, and in vitro release and lipolysis. Different formulations of 40 mg/kg baicalein were orally administered to Sprague-Dawley rats to investigate their respective bioavailabilities. The chylomicron flow blocking rat model was used to evaluate their lymphatic transport. The droplet sizes of BAPC-SMEDDS and CBA-SMEDDS after 100x dilution were 9.6±0.2 nm and 11.3±0.4 nm, respectively. In vivo experiments indicated that the relative bioavailability of CBA-SMEDDS and BAPC-SMEDDS was 342.5% and 448.7% compared to that of free baicalein (BA). The AUC and C of BAPC-SMEDDS were 1.31 and 1.87 times higher than those of CBA-SMEDDS, respectively. The lymphatic transport study revealed that 81.2% of orally absorbed BA entered the circulation directly through the portal vein, whereas approximately 18.8% was transported into the blood via lymphatic transport. CBA-SMEDDS and BAPC-SMEDDS increased the lymphatic transport ratio of BA from 18.8% to 56.2% and 70.2%, respectively. Therefore, self-microemulsion not only significantly improves oral bioavailability of baicalein, but also increases the proportion lymphatically transported. This is beneficial to the direct interaction of baicalein with relevant immune cells in the lymphatic system and for proper display of its effects. This study demonstrates the oral absorption and lymphatic transport characteristics of free baicalein and baicalein SMEDDS with different compositions. This is of great significance to studies on lymphatic targeted delivery of natural immunomodulatory compounds.

To investigate the targeting effect of toluidine blue-dextran-40 (TB-Dex-40) on the head and neck lymphatic system. Thirty healthy adult New Zealand white rabbits were randomly divided into two groups: the experimental group (TB-Dex-40 group, n = 15) and the control group (TB group, n = 15). In the experimental group, 1.0% TB-Dex-40 (0.14 mOsm/L) was submucosally injected at the lingual margin (1 cm from the tip of the tongue), while in the control group, 1.0% toluidine blue (32.60 mOsm/L) was administered under the same conditions. The time required for the dye to reach and stain the sentinel lymph node (SLN) was recorded, and the diffusion range of the dyes in the tongue was measured. SLN samples were collected at 30 min and 2 h post-injection for histopathological examination. SLN staining persistence was observed at 1 day, 2 days, and 4 weeks post-injection. Routine blood and biochemical tests were conducted before and 2 weeks after the experiment to evaluate systemic safety. Additionally, in two separate rabbits, the two dyes were injected into the common carotid artery to observe their effects on cervical lymph nodes, submandibular glands, and tongue tissue. A sucrose preference test was performed during animal rearing to assess potential neurotoxicity induced by the dyes. In the experimental group, it took (21.67 ± 0.19) seconds for the dye to reach the SLN and stain lymphatic vessels, which was significantly longer than that in the control group [(3.22 ± 0.34) seconds] ( P  < 0.01). The SLN stained in the experimental group remained clearly visible even after 4 weeks, whereas the SLN stained in the control group had completely faded by 2 days. The diffusion range of the dye in the tongue was significantly smaller in the experimental group [(10.53 ± 1.09) mm] compared with the control group [(20.04 ± 1.06) mm] ( P  < 0.01). No abnormalities were detected in the blood parameters of the experimental animals. Neither group exhibited neurological abnormalities. After injection via the common carotid artery, significant staining was observed in the lymph nodes of the TB group but not in the TB-Dex-40 group. TB-Dex-40 demonstrates superior targeting capabilities within the lymphatic system and holds substantial potential for clinical translation. Clinical relevance: TB-Dex-40 exhibits specificity for lymphatic vessels and serves as an effective tracer with significant clinical potential. Its molecular structure provides a robust theoretical foundation for the development of future imaging agents.

Background: Cannabidiol (CBD) exerts diverse metabolic effects, yet its influence on intestinal lipid metabolism remains unclear. Methods: In this study, we investigated whether short-term (one-week) CBD treatment affects lipid absorption and transport through the lymphatic system using a validated lymph fistula model. Results: CBD treatment significantly enhanced the transport of radiolabeled triglycerides through the lymphatic system. This effect appeared specific, as CBD did not substantially alter cholesterol output in the lymph. Chemical assays indicated that CBD treatment did not significantly alter total triglycerides, cholesterol, phospholipids, or non-esterified fatty acid levels in the lymph. However, it significantly enhanced the lymphatic output of apolipoprotein A4 (ApoA4) and apolipoprotein A1 (ApoA1). Additionally, gene expression analysis revealed a downregulation of vascular endothelial growth factor receptor 1 (Flt1) in the small intestine, leading to increased lymphatic lacteal permeability and altered lipid transport dynamics. Conclusions: These findings indicate that short-term CBD treatment modulates lymphatic lipid composition and apolipoprotein secretion by regulating lymphatic lacteal function, thereby influencing lipid transport and metabolism. This study provides novel insights into CBD’s role in facilitating TG-rich lipoprotein transport via the lymphatic system, highlighting its potential therapeutic applications in lipid-related disorders.