Lymphatic Drug Delivery Systems and Mechanisms

The lymphatic system comprises a network of vessels and lymph nodes that drains interstitial fluid, transports immune cells and absorbs dietary lipids via chylomicrons. Exploiting this pathway for therapeutic delivery can enhance bioavailability, bypass hepatic first-pass metabolism and achieve targeted accumulation in lymphoid tissues. Strategies include lipid-based nanocarriers such as liposomes and solid lipid nanoparticles that mimic chylomicron formation to promote intestinal uptake, polymeric micelles incorporating surface ligands for receptor-mediated entry, and prodrug approaches that increase lipophilicity to favour lymphatic partitioning. Self-microemulsifying drug delivery systems (SMEDDS) have been employed to form micro-droplets in the gut that are absorbed into mesenteric lymphatics, enhancing immunomodulator delivery to lymph nodes. Mechanistic insights have revealed the importance of particle size (generally below 100 nm), surface charge and hydrophobicity in traversing lymphatic capillaries, as well as the role of lymph flow rates and enzymatic digestion in drug release. Advanced modalities such as nano-fluorescence and photoacoustic imaging agents enable real-time monitoring of lymphatic transport and nodal targeting. Collectively, these systems offer promising avenues for cancer chemotherapy, immunotherapy and treatment of lymphatic disorders by achieving site-specific drug delivery with reduced systemic exposure.

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Lymphatic Drug Delivery Systems and Mechanisms publication trend

The graph below shows the total number of articles in lymphatic drug delivery systems and mechanisms across all publications each year (not limited to Nature Index journals).

Technical terms

Nanocarrier: A nanoscale vehicle (e.g. liposome, polymeric particle) engineered to encapsulate drugs and facilitate targeted delivery via the lymphatic system.

Chylomicron: A lipid–protein complex produced by enterocytes to transport dietary fats, which can be hijacked by lipophilic drugs for intestinal lymphatic uptake.

Self-microemulsifying drug delivery system (SMEDDS): A formulation of oils, surfactants and co-solvents that spontaneously forms fine oil-in-water emulsions in the gastrointestinal tract to enhance lymphatic absorption of lipophilic drugs.

Lymphatic capillaries: Small, blind-ended vessels that absorb interstitial fluid and particulates, providing the primary entry route for nanoparticle-based therapies into the lymphatic network.

References

1. Multifunctional nanocarriers for targeted drug delivery and diagnostic applications of lymph nodes metastasis: a review of recent trends and future perspectives. Journal of Nanobiotechnology (2023).
2. Nano-fluorescence imaging: advancing lymphatic disease diagnosis and monitoring. Nano Convergence (2024).
3. Liposomal delivery systems for intestinal lymphatic drug transport. Biomaterials Research (2016).
4. Lipophilic activated ester prodrug approach for drug delivery to the intestinal lymphatic system. Journal of Controlled Release (2018).
5. Metastatic status of sentinel lymph nodes in breast cancer determined with photoacoustic microscopy via dual-targeting nanoparticles. Light: Science & Applications (2020).
6. Efficient Intestinal Digestion and On Site Tumor‐Bioactivation are the Two Important Determinants for Chylomicron‐Mediated Lymph‐Targeting Triglyceride‐Mimetic Docetaxel Oral Prodrugs. Advanced Science (2019).
7. Intestinal Lymph Flow, and Lipid and Drug Transport Scale Allometrically From Pre-clinical Species to Humans. Frontiers in Physiology (2020).
8. Oral SMEDDS promotes lymphatic transport and mesenteric lymph nodes target of chlorogenic acid for effective T-cell antitumor immunity. Journal for ImmunoTherapy of Cancer (2021).