Editorial Feature

How Are Lipid Nanoparticles Metabolized?

Continue reading to learn about the conventional routes of how lipid nanoparticles are metabolized.

Lipid nanoparticle mRNA vaccine entering a human cell, a type of vaccine used against Covid-19. 3D illustration showing cross-section of a lipid nanoparticle carrying mRNA of the virus (orange).

Image Credit: Kateryna Kon/Shutterstock.com

Lipid nanoparticles have gained popularity in drug development research due to their suitability as nanocarriers for drugs with poor availability in the body. Additionally, their remarkable physicochemical characteristics demonstrate the potential of lipid nanoparticles in improving the stability, solubility and permeability of carried drugs to ensure their release and metabolization at the target site effectively.[1]

Introduction to Lipid Nanoparticles

Lipid nanoparticles consist of spherical vesicles made of ionizable lipids with a positive charge at a low pH level, while being neutral at a physiological pH. Such a characteristic enables RNA complexation and decreases potential toxicity.[2]

Additionally, their small size, between 10 and 1000 nm and other attributes, enable cell lipid nanoparticle uptake through endocytosis.[2,3] It is theorized that the ionizability of the lipids at a low pH allows for endosomal escape, which permits the cargo to be released into the cytoplasm.[2]

Metabolism of Lipid Nanoparticles in Biological Systems

Nanocarrier metabolism comprises any process that results in the loss of the lipid nanoparticle’s original form, which includes the degradation of its components and drug release.[4]

Lipid nanoparticles can be biodegraded into hydrophilic small molecules for the process of excretion to occur, with their exogenous metabolites then being excreted through urine or bile. However, with some metabolites having pharmacological or toxicological activity that affects the functionality of drug transporters and metabolic enzymes, this can lead to potential toxicity when the lipid nanoparticles are metabolized.[4]

Biodegradable nanocarriers can have varied metabolism due to their chemical composition and physiochemical characteristics. Nanoparticles made of neural and hydrophilic materials can avoid macrophage uptake effectively and quickly degrade into metabolites. There are also some conventional long-chain polymers that do not degrade when in a biological environment and can stay in the body.[4]

Routes of Metabolism for Lipid Nanoparticles

Lipid nanoparticles have various metabolism routes, which can depend on the delivery method and target site. These routes include oral, intravenous, transdermal and intramuscular delivery systems and consist of many physical, chemical and biological barriers for the lipid nanoparticles to overcome before reaching the target site.[5]

The oral route, which is most popular for drug administration, comprises physical barriers in the body, including the peristalsis, the mucus layer, and the gastrointestinal epithelium. The chemical barriers that can be a threat to lipid nanoparticles include pH changes and surfactants such as bile salts. In contrast, the biological barriers comprise the immune system itself, digestive enzymes, the effect of first-pass metabolism and the microbiota activity.[5]

These barriers can metabolize lipid nanoparticles pre-emptively, resulting in the nanoparticles being in the body for a shorter period due to being metabolized quickly. However, an advantage of the oral route of administration is that it can be self-administered by the patient, which can increase patient compliance, bypassing first-pass hepatic effects and providing a good surface for absorption.[5]

The intravenous route is the most common administration route for nanomaterial-based anticancer drugs, and bypasses most physical and chemical barriers. An advantage of this route includes providing the most direct pathway to the systemic circulatory system.[5]

The transdermal route also consists of barriers, with physical barriers such as the epithelium, epidermis, dermis and hypodermis being obstacles. Biological barriers include the immune system, which can break down the lipid nanoparticles as a foreign body.[5]

However, there are advantages of the transdermal route, including being self-administered by the patient, bypassing first-pass metabolism, and providing a sustained and continuous release of drugs.[5]

The intramuscular route of administration can have physical barriers, such as the extracellular matrix and blood and lymphatic vessels, while the chemical and biological barriers include enzymes and the immune system, respectively. This delivery route can also be beneficial, with patient self-administration possible, as well as bypassing the first-pass metabolism effect.[5]

Factors Affecting Lipid Nanoparticle Metabolism

There are many factors that can impact lipid nanoparticle metabolism, including the use of PEG-lipids, which can have several effects on the properties of lipid nanoparticles. PEG-lipids can affect particle size, while also increasing particle stability by decreasing particle aggregation.[5]

Additionally, PEG modifications can increase the amount of time nanoparticles circulate in the blood by decreasing blood clearance, which is mediated by the kidneys and the mononuclear phagocyte system.[5]

Targeting ligands on the surface of lipid nanoparticles can also increase the uptake of the particles into specific cells, affecting distribution and metabolism in vivo.[5]

Implications and Applications in Drug Delivery and Therapeutics

Lipid-based nanocarriers have become landmarks in the advancement of drug delivery, with research leading to the development of Doxil®, which was the first lipid-based nanocarrier that received Food and Drug Administration (FDA) approval.[1]

The advancement of lipid nanoparticles for drug delivery has progressed over the years, with various delivery routes also being explored. Intracerebroventricular injection enables drugs to be delivered into the brain via the cerebrospinal fluid, which can bypass the blood brain barrier (BBB).[6]

This is typically difficult for traditional drugs that are too large and can have significant implications for drug delivery and therapeutics, such as the treatment of brain cancer, with drugs that are encapsulated in solid lipid nanoparticles.[6]

Lipid nanoparticles have demonstrated some advantages compared to polymeric and inorganic nanoparticles, and this has spearheaded research into the applications of lipid nanoparticles, with further work focusing on optimizing formulations that will enhance their stability, metabolism and therapeutic applications, such as brain uptake.[5,6]

References and Further Reading

  1. Plaza-Oliver M, Santander-Ortega MJ, Lozano M.Victoria. Current approaches in lipid-based nanocarriers for Oral Drug Delivery. Drug Delivery and Translational Research. 2021;11(2):471-497. doi:10.1007/s13346-021-00908-7
  2. Let’s talk about lipid nanoparticles. Nature Reviews Materials. 2021;6(2):99-99. doi:10.1038/s41578-021-00281-4
  3. Mukherjee S, Ray S, Thakur R. Solid lipid nanoparticles: A modern formulation approach in drug delivery system. Indian Journal of Pharmaceutical Sciences. 2009;71(4):349. doi:10.4103/0250-474x.57282
  4. Zhang A, Meng K, Liu Y, et al. Absorption, distribution, metabolism, and excretion of nanocarriers in vivo and their influences. Advances in Colloid and Interface Science. 2020;284:102261. doi:10.1016/j.cis.2020.102261
  5. Graván P, Aguilera-Garrido A, Marchal JA, Navarro-Marchal SA, Galisteo-González F. Lipid-core nanoparticles: Classification, Preparation Methods, routes of administration and recent advances in cancer treatment. Advances in Colloid and Interface Science. 2023;314:102871. doi:10.1016/j.cis.2023.102871
  6. Fernandes F, Dias-Teixeira M, Delerue-Matos C, Grosso C. Critical review of lipid-based nanoparticles as carriers of neuroprotective drugs and extracts. Nanomaterials. 2021;11(3):563. doi:10.3390/nano11030563

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Marzia Khan

Written by

Marzia Khan

Marzia Khan is a lover of scientific research and innovation. She immerses herself in literature and novel therapeutics which she does through her position on the Royal Free Ethical Review Board. Marzia has a MSc in Nanotechnology and Regenerative Medicine as well as a BSc in Biomedical Sciences. She is currently working in the NHS and is engaging in a scientific innovation program.


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