Breaking the Blood-Brain Barrier: Liposome Targeted Delivery Technology Reshaping the Treatment Landscape of Alzheimer’s Disease

Although the relationship between β-amyloid protein deposition and the formation of hyperphosphorylated Tau protein and neurofibrillary tangles and Alzheimer’s disease has been elucidated, current treatments can only alleviate symptoms but cannot cure it. Researchers and clinicians commonly aim to identify effective treatments that target disease root causes. The advanced drug delivery system known as liposomes has demonstrated substantial potential for treating Alzheimer’s Disease in recent scientific developments. These systems allow loading multiple active substances for targeted delivery while enhancing targeting and BBB penetration through surface modification to ensure precise drug delivery to specific brain locations. Through surface modification liposomes can be engineered to selectively attach to Aβ for removal and block Tau protein aggregation while targeting other Alzheimer’s disease (AD) markers. This article focuses on presenting the current advancements of liposome technology for Alzheimer’s Disease treatment while examining their benefits as a delivery system and pointing out existing challenges along with future research paths.

Structure and Modification of Liposomes

Basic Structure and Composition

Liposomes comprise one or multiple enclosed microvesicles constructed from phospholipid bilayers leading to the formation of unilamellar liposomes and both multilamellar liposomes. The single phospholipid bilayer of unilamellar liposomes with small diameters enables them to carry both small molecule drugs and large biomacromolecules. Multilamellar liposomes (MLV) consist of multiple phospholipid bilayers and measure from 100 to 1000 nanometers in size. The structural organization shows multiple layers similar to an onion’s structure. Each layer of the multilamellar liposome structure can store water-soluble drugs making it ideal for delivering multiple medications in combination therapies. Phospholipids and cholesterol build liposomes along with additional supporting components.

Surface Modification

A vital technical technique to modify liposomes involves attaching molecules to their surface. PEGylation remains the most important liposome surface modification method because it improves liposome stability in the bloodstream while reducing reticuloendothelial system clearance thereby prolonging their circulation time. The intentional modification of liposome surfaces with targeting ligands like antibodies allows for their active attachment to cell surface receptors which enables targeted delivery. Scientists can develop drug release systems by connecting liposomes with thermosensitive or pH-sensitive materials which activate drug discharge upon changes in environmental temperature or pH levels.

Advantages of Liposomes in Drug Delivery

Liposomes can provide protection for hydrophilic drugs and make them more stable in the body; while for hydrophobic drugs, liposomes can improve their water solubility and improve their distribution and absorption in the body. This will increase the bioavailability of drugs in the body. Liposomes provide sustained drug release alongside controlled drug delivery while supporting stable drug concentrations and extended drug action duration for treatments needing long-term effectiveness. Liposomes stand out as advanced drug delivery systems because their distinct structure and preparation adaptability deliver significant benefits in biocompatibility, sustained release, drug targeting and protection which open new treatment possibilities for numerous diseases particularly where biological barrier crossing or precise drug delivery is required thus showing extensive application potential.

Liposomes have Emerged as a Therapeutic Tool in Alzheimer’s Disease Treatment

The targeted treatment approach for Alzheimer’s Disease reveals high potential for liposomes and modified liposomes. The modification of liposomes includes adding molecules to their surface and encapsulating drugs within the vesicle’s water core or lipid bilayer while also modifying specific ligands or antibodies to target brain lesions in AD patients like Aβ plaques or Tau protein aggregation sites for accurate drug delivery that enhances therapeutic effects and minimizes normal tissue side effects. A single PEG modification enhances both water solubility and stability of drugs while PEG-linked peptides and antibodies alongside glutathione (GSH), surface antibodies, lactoferrin, glucose, wheat germ agglutinin, and transferrin (Tf) aid drug crossing of the BBB and phosphatidic acid, PEG-curcumin, lipophilic peptides, lipophilic drugs, hydrophilic peptides, hydrophilic drugs, and nucleic acids actively participate in targeted AD treatment forming an effective therapy strategy. These innovative technologies and modifications enhance drugs’ stability and bioavailability while facilitating their penetration through the BBB and enabling effective brain delivery to produce a synergistic therapeutic impact. Tab. 1 Application of liposomes in the treatment of Alzheimer’s disease

Single-Target Ligand Modification

Glutathione The naturally occurring tripeptide GSH consists of glutamic acid, cysteine, and glycine. The molecule serves as a crucial antioxidant within cellular structures and assumes a significant function in numerous physiological functions. GSH-modified liposomes represent a drug delivery technology that takes advantage of GSH’s unique properties to improve delivery efficiency. Research teams developed GSH-PEG liposomes for transporting anti-amyloid single-domain antibody fragments known as VHH-pa2H through the BBB into the brain. Researchers prepared two formulations of GSH-PEG liposomes which used dimyristoylphosphatidylcholine (DMPC) and egg yolk phosphatidylcholine (EYPC) and encapsulated VHH-pa2H within them before labeling the antibody fragment with indium-111 to study its biodistribution. Encapsulation of VHH-pa2H in GSH-PEGEYPC liposomes resulted in a 4 times higher concentration in the brains of AD mouse models compared to free VHH-pa2H and showed enhanced retention and targeting of antibody fragments. Glucose Glucose functions as the brain’s primary energy source while the brain itself lacks the ability to produce glucose. The movement of glucose through the brain capillary walls requires the glucose transporter (Glut) present on the endothelial cells. The glucose-modified liposomes technology improves liposome functionality through their ability to attach to glucose molecules. Glut expression levels in the brain and its high transport efficiency make it possible for glucose modification to enhance liposomal brain targeting which then delivers drugs more effectively to AD patient brains for lesion area treatment. Glucose modification enhances liposome biocompatibility and stability which results in prolonged drug circulation time throughout the body while reducing immune system reactions. Transferrin Transferrin exists abundantly within the bloodstream. Transferrin functions as an iron ion transporter and possesses its specific transferrin receptor (TfR) in numerous cell types. The receptor shows high expression levels in brain cells particularly on BBB endothelial cells. Transferrin-modified liposomes enhance drug delivery to the brain by binding to TfR which enables drugs to cross the BBB and become essential tools for treating central nervous system diseases such as AD. Apolipoprotein E Apolipoprotein E ApoE functions as a protein that occurs throughout the entire body. Apolipoprotein E plays a critical function in lipid metabolism and cholesterol transport while showing strong connections to AD pathogenesis. Among the ApoE variants linked to Alzheimer’s disease risk, ApoE4 stands out by causing brain Aβ aggregation and escalating AD susceptibility. The targeting ligands modification process utilizes ApoE to enhance liposome delivery to brain lesion areas in AD patients by facilitating BBB crossing through low-density lipoprotein receptor binding and enabling controlled drug release in response to specific lesion conditions.

Multi-Target Liposomes

Liposomes with Curcumin Derivatives and Brain-Targeting Functions The natural polyphenol compound Curcumin (CURC) originates from turmeric rhizomes. CURC demonstrates potent antioxidant properties that enable it to eliminate free radicals thereby protecting neurons from oxidative stress-induced damage. CURC and its derivatives attach to Aβ peptides which disrupts their aggregation resulting in fewer Aβ plaque formations. The water solubility and bioavailability of CURC remain low when not encapsulated. Encapsulation of CURC in liposomes improves its solubility and stability while increasing bioavailability and enabling targeted delivery which enhances its therapeutic efficacy. The research team created brain-specific multifunctional nanoliposomes DPS-PEG2000-CURC NLs containing CURC derivatives to target Aβ deposits in Alzheimer’s disease brains. PEG modification sustains liposomes in the bloodstream longer and improves their stability at the same time CURC modification allows liposomes to block Aβ aggregation. The researchers increased nanoliposomes’ BBB penetration capability by attaching a BBB transport mediator anti-TfR monoclonal antibody (MAb) to their surface. The multifunctional nanoliposomes exhibited both anti-Aβ aggregation effects and successful BBB crossing abilities in experimental results. Bionic Exosome-Liposome Hybrid Nanovesicles Scientists designed a ROS-responsive bionic nanovesicle system called TSEL: The researchers began by preparing a liposome film from a lipid mixture via rotary evaporation which allowed the loading of pTREM2 and siBACE1 into liposomes’ hydrophilic space through a hydrated lipid film before extracting exosomes from MSC supernatants using ultracentrifugation and combining them with drug-loaded liposomes to form hybrid nanovesicles. Nanovesicles combine exosome homing ability with Ang2 assistance to cross the BBB and concentrate in the AD lesion area. The expression of TREM2 can switch microglia from M1 pro-inflammatory state to M2 anti-inflammatory state which restores Aβ phagocytosis and neurorepair functions. The therapeutic effect of AD treatment improves when siRNA reduces Aβ plaque formation through BACE1 gene knockdown.