Lipid nanoparticle-mediated drug delivery to the brain (2023)

partial fragment

Prevalence of central nervous system disorders and delivery challenges

According to UN statistics, as many as 1 billion people suffer from neurological disorders [1], [2]. From 1990 to 2017, the prevalence and mortality of almost all neurological diseases increased dramatically [3]. Common disorders of the central nervous system include Alzheimer's disease (advertise), Parkinson's disease (Partial discharge), multiple sclerosis, stroke, epilepsy and migraine [2]. Stroke, Alzheimer's disease and migraine identified as top three neurological disorders, based on

General composition and structure of LNPs

The development of LNPs can be traced back to the 1990s, when the Cullis group pioneered the study of pH-sensitive LNPs [70]. LNPs consist of an outer layer of a mixture of functional and accessory lipids. Functional lipids consist primarily of ionizable cationic lipids, while accessory lipids include distearoylphosphatidylcholine (DSPC), dioleoylphosphatidylcholin (DOPC), dioleoylphosphatidylethanolamin (coating), stearoyl oleoyl phosphorylcholin (enkelt chip microcomputer), polyethylenglycol-lipid (PEG-lipid),

Apolipoprotein E (apoE)-mediated uptake of LNP by hepatocytes: what implications does this mechanism have for brain delivery?

postali.v.After administration, the adsorption of apoE to the surface of LNPs has been shown to be critical for its uptake into hepatocytes/hepatocytes [115]. The resulting apoE-LNP complexes act as ligands for lipoprotein receptors on hepatocytes, allowing their uptake by endocytosis and accumulation in the liver [50]. Therefore, it is not surprising that LNPs naturally target the liver. Intravenous administration of LNP is the preferred route of administration due to the relatively increased number of patients

Ligand-functionalized LNPs for delivery via the BBB

Functionalization of nanoparticle systems with targeting ligands can be used to achieve site-specific delivery, increase uptake into target cells and reduce off-target effects [126] , [127] . LNPs have been surface functionalized by modifying targeting ligands and antibodies for drug delivery to non-CNS sites such as tumors, bone marrow cells, gliomas, adipocytes and hepatocytes [126], [127], [128], [129], [130] ] As mentioned in section 3, afteri.v.When administered, apoE adsorbs to

Ionic liquids (ILs) and their ability to redirect LNP biodistribution to the brain

Ionic liquid (ILs) has recently emerged as a class of biomaterials that can be administered via a variety of routes such as transdermal [142], [143], [144], [145], oral [146], intranasal [147] and buccal [ 148] ], [149]. Ionic liquids are salts that are viscous liquids below 100 °C and are composed of bulky and asymmetric anions and cations [150], [151], [152]. Anion-cation coordination

Considerations, open questions and potential opportunities

The mystery of apoE-driven LNP uptake for brain delivery.A lotin vitroStudies have used apolipoprotein E-coated nanoparticles to transport molecules in cultured BEC monolayers [123] , [196] , [197] , [198] . It should be noted that apoE receptors belong to the family of low-density lipoprotein receptors involved in receptor-mediated endocytosis [199]. Receptor-mediated endocytosis occurs through invagination of the plasma membrane, resulting in the formation of clathrin-coated pits [200], [201]


Ionizable cationic lipid-based LNPs are effective vehicles for the delivery of macromolecules such as mRNA, siRNA and proteins to muscle and liver targets. However, there are few reports on drug delivery to extrahepatic targets, especially the brain, via LNPs. LNPs allow high drug loading, which is a major advantage even with low brain tissue uptake. Therefore, the high drug loading of LNPs makes them interesting vehicles for drug delivery to the brain

Statement of competing interests

The authors declare that they have no known competing financial interests or personal relationships that could influence the work reported in this article.

thank you

This work was supported by start-up funds from Duquesne University's (DU) Manickam Laboratory, a 2021 Faculty Development Fund (DU Office of Research), and PI's Charles Henry Leach II grant. Purva Khare and Devika S Manickam would like to thank Dr. Lauren O'Donnell (Dukein University, Pittsburgh, PA) for helpful discussions.

declaration of interest: nobody

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What is lipid nanoparticles for drug delivery brain? ›

Nanoparticles for drug delivery to the brain is a method for transporting drug molecules across the blood–brain barrier (BBB) using nanoparticles. These drugs cross the BBB and deliver pharmaceuticals to the brain for therapeutic treatment of neurological disorders.

Can nanoparticles enter the brain? ›

After entering the body, nanoparticles can reach the organs through systemic circulation. Furthermore, depending on their characteristics, such as size, shape, and chemical reactivity, they can cross the blood-brain barrier, or they can reach the brain through axonal transport along the olfactory nerve [17].

What are liposome nanoparticles for drug delivery? ›

Liposomes protect the loaded drug molecules from external degradation, and their similarity to biological membranes provides unique opportunities to deliver drug molecules into the cells or their sub-cellular compartments.

What is the maximum size of nanoparticles which will allow delivery to the brain? ›

NPs are typically by a size measuring not more than 100 nm and have significant potential for delivering drugs across the blood-brain barrier. The size of quantum dots is usually less than 10 nm.

What are the side effects of nanoparticles in drug delivery? ›

The effects of inhaled nanoparticles in the body may include lung inflammation and heart problems. Studies in humans show that breathing in diesel soot causes a general inflammatory response and alters the system that regulates the involuntary functions in the cardiovascular system, such as control of heart rate.

What are the disadvantages of lipid nanoparticles? ›

The flawless crystalline structure of SLNs has several drawbacks as well, including a low drug loading efficiency and the potential for drug expulsion due to crystallization during storage. Lipid dispersions have high water content. Limited transdermal medication delivery.

Do nanoparticles change your DNA? ›

Some nanoparticles, if they're based on certain metals, can interact with the hydrogen peroxide that is present in every cell, and convert it to a hydroxyl radical, which can enter the nucleus and then you potentially have DNA damage. How do nanoparticles get inside cells?

How do you get rid of nanoparticles in your body? ›

Even insoluble nanoparticles which reach the finely branched alveoli in the lungs can be removed by macrophage cells engulfing them and carrying them out to the mucus, but only 20 to 30 per cent of them are cleared in this way. Nanoparticles in the blood can also be filtered out by the kidneys and excreted in urine.

How long do nanoparticles stay in your system? ›

The blood half-lives of the various iron oxide nanoparticles currently in clinical use vary from 1 h to 24-36 h [69]. However, specific biodistribution and clearance parameters depend on particle properties such as surface characteristics, shape, and size [71].

What are the disadvantages of liposomal drug delivery system? ›

Disadvantages Of Liposomes

Lipid based drug delivery system are expensive to produce, hence the production cost is high. The cost is high because of high costs associated with the raw materials used in lipid excipients as well as expensive equipment needed to increase manufacturing [41].

What are the major disadvantages of using liposomes as targeted drug delivery vehicle? ›

Disadvantages of liposomes

Production cost is high. Leakage and fusion of encapsulated drug / molecules. Sometimes phospholipid undergoes oxidation and hydrolysis-like reactions. Short half-life.

How does nanoparticle drug delivery work? ›

Nanoparticles can enter the human body, via three main route, direct injection, inhalation and oral intake. Once, they enter systemic circulation, particle-protein interaction is the first phenomenon taking place before distribution into various organs (Mu et al., 2014, Prado-Gotor and Grueso, 2011).

Can lipid nanoparticles cross blood-brain barrier? ›

Due to their size and properties, lipid nanoparticles, therefore, can interact as a drug carrier molecule with the BBB and its components, and cross the BBB.

Can nanoparticles cross blood-brain barrier? ›

Nanoparticles are small sized (1-100 nm) particles derived from transition metals, silver, copper, aluminum, silicon, carbon and metal oxides that can easily cross the blood-brain barrier (BBB) and/or produce damage to the barrier integrity by altering endothelial cell membrane permeability.

Do liposomes cross the blood-brain barrier? ›

Abstract. Liposomes are clinically used drug carriers designed to improve the delivery of drugs to specific tissues while minimising systemic distribution. However, liposomes are unable to cross the blood-brain barrier (BBB) and enter the brain, mostly due to their large size (ca. 100 nm).

What medicines contain nanoparticles? ›

Several anti-cancer drugs including paclitaxel, doxorubicin, 5-fluorouracil and dexamethasone have been successfully formulated using nanomaterials. Quantom dots, chitosan, Polylactic/glycolic acid (PLGA) and PLGA-based nanoparticles have also been used for in vitro RNAi delivery.

Which nanoparticle is best for drug delivery? ›

Polymeric nanoparticles can be categorized into nanospheres and nanocapsules both of which are excellent drug delivery systems. Likewise, compact lipid nanostructures and phospholipids including liposomes and micelles are very useful in targeted drug delivery.

What can nanoparticles cause damage of? ›

Nanoparticles can cause DNA damage across a cellular barrier.

Can lipid nanoparticles damage DNA? ›

Since it is now known that the nanoparticles induce DNA damage in several ways, it becomes crucial to understand how these NPs interact with the DNA and its associated set of proteins to hinder the repair mechanism and cause DNA damage finally.

Are lipid nanoparticles magnetic? ›

Cellular uptake by MCF-7 cells experiment presented the excellent internalization ability of the prepared magnetic lipid nanoparticles. These results evidenced that the present magnetic lipid nanoparticles have potential for targeting therapy of antitumor drugs.

What are the most harmful nanoparticles? ›

Our results indicate that, out of all nanoparticles studied, Copper- and Zinc-based nanomaterials present the highest toxicity, whatever their oxidation status.

How do you detect nanobots in your body? ›

Magnetic Resonance Imaging (MRI) devices could also be employed to track the position of nanobots, and early experiments with MRIs have demonstrated that the technology can be used to detect and even maneuver nanobots.

Do nanoparticles emit radiation? ›

Light bright: Nanoparticles emit unique wavelengths of light when struck by a common source of radiation. These waves can be detected as different colors by clinical scanners.

What is the effect of nanoparticles on the cell life cycle? ›

Higher doses of a toxic nanoparticle or testing a long time after manipulation may lead to more cell death, either apoptosis which might be evident in sub G1 peaks or necrosis, thus possibly masking underlying cell cycle dysregulation.

Can nanoparticles control humans? ›

These nanoparticles are engineered to seek out tumor cells and destroy or used as an injectable, reversible male contraception. But, in the future, gold nanoparticles could even be used to control our brain — or rather, to activate brain cells remotely and help treat neurological disease.

What is the fate of nanoparticles in human body? ›

Nanoparticles are known to induce inflammation in the lung, and some reports of pulmonary fibrosis are available. There are indications that nanoparticles penetrate vascular tissue and therefore trigger certain dysfunc- tions or influence the cardiovascular sys- tem.

How are humans exposed to nanoparticles? ›

Inhalation is the primary route of human exposure to nanoparticles. The different compartments of the human respiratory tract (nose, larynx, airways, lungs) all act as a filter for nanoparticles. The smaller the particle, the more likely its chance to reach the lung.

How do you check for drug release from nanoparticles? ›

The DM method is the most popular method to test the in vitro release kinetics of nanoparticles. Irrespective of the different set-ups, they all rely on a semi-permeable membrane to achieve physical separation of the nanoparticle and the free drug.

Where do nanoparticles accumulate in the body? ›

Degradable assemblies or aggregates of nanoparticles are necessary to study this effect because, as discussed above, very small nanoparticles are primarily excreted through the kidneys and have low liver accumulation while larger nanoparticles accumulate in the liver but have minimal clearance.

How do I disable Nanobots? ›

Ferrous nanoparticles

In case of failure or malfunction, a small EMP or an MRI could be used to deactivate the nanobots. Both techniques induce an electromagnetic field, corrupting the memory and shorting out the circuitry of any electronic device within range.

What are the dangers of liposomal? ›

Possible Side Effects of Liposomal Doxorubicin (Doxil) (Table Version Date: July 7, 2022)
  • Infection, especially when white blood cell count is low.
  • Bruising, bleeding.
  • Anemia which may require blood transfusions.
  • Vomiting, nausea, constipation or diarrhea.
  • Sores in mouth which may cause difficulty swallowing.
  • Fever.

Are liposomes toxic to cells? ›

While liposomes are typically considered pharmacologically inactive with minimal toxicity [2,21], their toxicity is tightly related to the type of model, exposure time, dose, and/or surface properties.

What is the conclusion for liposomal drug delivery system? ›

The liposomal drug delivery system has several advantages of being biocompatible, low toxicity, stability against chemical degradation, and site-specific targeting [20]. Liposomes are promising drug carriers, for the treatment and prevention of malaria and also for vaccine delivery [19].

What is liposomes for brain targeted drug delivery? ›

The most successful strategy for liposome delivery to the brain consists on binding over the liposomes' surface a biologically active ligand (peptides, antibodies or small molecules) with receptors on the surface of BBB. In this way, liposomes can enter the CNS by receptor-mediated transcytosis.

What are the disadvantages of liposome mediated gene transfer? ›

Liposome-mediated transfection of endothelial cells provides a valuable experimental technique to study cellular gene expression and may also be adapted for gene therapy studies. However, the widely recognized disadvantage of liposome-mediated transfection is low efficiency.

How drugs are loaded in liposomes? ›

In active loading, drug internalization into preformed liposomes is typically driven by a transmembrane pH gradient. The pH outside the liposome allows some of the drug to exist in an unionized form, able to migrate across the lipid bilayer.

What are the advantages of nanoparticle drug delivery? ›

Improved efficacy by controlled delivery of the therapeutic agent. Targeted and controlled release of the drug, improved anticancer efficacy, decreased systemic toxicity. Enhanced solubility; Increased delivery to the tumor. Improved drug loading and bioavailability; Slow release.

How nanotechnology is safe for drug delivery? ›

The technology enables the delivery of drugs that are poorly water soluble and can provide means of bypassing the liver, thereby preventing the first pass metabolism Nanotechnology increases oral bioavailability of drugs due to their specialized uptake mechanisms such as absorptive endocytosis and are able to remain in ...

Which disease is associated with nanoparticle exposure on brain linked to? ›

The nanoparticles, even at lower concentrations could lead to hazardous impacts in the context of neurodegenerative disorders like Parkinson's disease and Alzheimer's disease (Campbell, 2004).

Does lipids affect the brain? ›

These lipids are involved in developmental, maintenance and many other cellular processes of the brain. The lipids act as signaling molecules, source of energy, for contributing to synaptogenesis, neurogenesis, impulse conduction and many others [1, 7].

Can lipids enter the brain? ›

How Do Lipids Enter the Brain? Lipids and lipid intermediates are essential components of the structure and function of the brain. In fact, the brain has the second highest lipid content behind adipose tissue, and brain lipids constitute 50% of the brain dry weight (9).

What happens if nanoparticles enter the brain? ›

The administration of titanium oxide nanoparticles through any route leads to the absorption and translocation into the brain, which can affect brain development and function. Furthermore, they can cross the placental barrier and accumulate in the fetal brain, causing impairments in the fetal brain development [87].

How are nanoparticles delivered to the brain? ›

The mechanism for the transport of polymer-based nanoparticles across the BBB has been characterized as receptor-mediated endocytosis by the brain capillary endothelial cells. Transcytosis then occurs to transport the nanoparticles across the tight junction of endothelial cells and into the brain.

Do nanoparticles may build up in the brain or liver? ›

Once they reach the blood circulation, NPs can be distributed and can accumulate in different organs such as the liver, spleen, lungs and kidneys. Some studies suggest that NPs may also accumulate in the brain if they are small enough (<10 nm) and/or the blood brain barrier is not intact.

Can lipid soluble drugs enter the blood-brain barrier? ›

However, a drug taken up by the membranes that form the BBB must then partition into the aqueous environment of the brain's interstitial fluid to exert an effect. As a result, a substance that is too lipid soluble can be sequestered by the capillary bed and not reach the cells behind the BBB.

What are 3 substances that can cross the blood-brain barrier? ›

Small polar molecules, such as glucose, amino acids, organic anions and cations, and nucleosides, can cross the blood-brain barrier by carrier-mediated transport.

Can lipid soluble drugs cross blood-brain barrier? ›

Generally, only lipid soluble (lipophilic) molecules with a low molecular weight (under 400–600 Da) and of positive charge can cross the BBB.

What is the use of nanoparticle in drug delivery? ›

Polyamidoamine nanoparticles work as nanocarrier and deliver anti-malarial drug to the targeted sites. It also works as nanomedicine. Union of doxorubicin and polymers increases drug solubility, enhances its blood half-life, decreases toxicity, and enhances targeting.

What is the role of nanoparticles in drug delivery system? ›

Due to their small size and large surface area, drug nanoparticles show increase solubility and thus enhanced bioavailability, additional ability to cross the blood brain barrier (BBB), enter the pulmonary system and be absorbed through the tight junctions of endothelial cells of the skin (Kohane, 2007).

What are nanoparticles for smart drug delivery? ›

Smart nanoparticles are those that are capable of releasing more drug molecules to the surrounding environment upon stimulation. The stimuli include physical (temperature, light, magnetic field, and electricity), chemical (pH, and ions), and biological (enzymes, antibodies, and small molecules) components.

What is the use of lipid in brain? ›

Lipids have multiple functions in brain

They have two principal functions in the body: as repositories of chemical energy in storage fat, primarily triglycerides, and as structural components of cell membranes.

Which nanoparticles are FDA approved? ›

Table 1 List of FDA-approved nanotechnology-based products and clinical trials.
Polymer nanoparticles-synthetic polymer particles combined with drugs or biologics
NameMaterial description
DaunoXome® (Galen)Liposomal daunorubicin
DepoCyt© (Sigma-Tau)Liposomal cytarabine
Marqibo® (Onco TCS)Liposomal vincristine
55 more rows

How nanoparticles are excreted from body? ›

Even insoluble nanoparticles which reach the finely branched alveoli in the lungs can be removed by macrophage cells engulfing them and carrying them out to the mucus, but only 20 to 30 per cent of them are cleared in this way. Nanoparticles in the blood can also be filtered out by the kidneys and excreted in urine.

What drugs have nanoparticles? ›

Several anti-cancer drugs including paclitaxel, doxorubicin, 5-fluorouracil and dexamethasone have been successfully formulated using nanomaterials. Quantom dots, chitosan, Polylactic/glycolic acid (PLGA) and PLGA-based nanoparticles have also been used for in vitro RNAi delivery.

What is the most important lipid in the brain? ›

Cholesterol is the most important component and fundamental functional unit of the mammalian cell membrane [16]. Most of the body cholesterol resides in brain in the form of myelin [17] which contains almost 80% of cholesterol found in adult brain [13].

What are the best lipids for the brain? ›

Monounsaturated and polyunsaturated fats are known as good fats. They can help the brain function more efficiently. A good source of healthy fats can be found in fish, olive oil, avocados and nuts.

Why do lipids cross the blood brain barrier? ›

Small, lipid soluble molecules can readily cross the membranes which form the BBB. Lipids, lipoproteins, and apolipoproteins that can cross the BBB do so largely by using saturable transporters.


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