Nanoparticles for Crossing the Blood–Brain Barrier in Alzheimer’s Disease Treatment

Alzheimer's disease (AD) is the most common form of dementia, responsible for approximately 60–70% of all dementia cases globally. Characterized by progressive cognitive decline, memory loss, and changes in personality, AD poses a significant public health challenge, particularly among aging populations. The World Health Organization reports that more than 55 million people are currently living with dementia, and this number is expected to surge to 152 million by 2050 due to increased life expectancy worldwide. The pathophysiology of AD is complex and involves several key features, including the accumulation of amyloid-beta (Aβ) plaques in the extracellular space, the formation of neurofibrillary tangles from hyperphosphorylated tau protein inside neurons, oxidative stress, neuroinflammation, and the degeneration of cholinergic neurons. Despite years of extensive research, existing treatments—primarily acetylcholinesterase inhibitors and NMDA receptor antagonists—only provide temporary symptom relief without addressing the underlying disease progression. One major challenge in developing effective AD treatments is the blood-brain barrier (BBB), a highly selective interface composed of endothelial cells, pericytes, astrocytic end-feet, and a basement membrane. This barrier restricts the entry of most therapeutic agents, including peptides, antibodies, and small-molecule drugs, with over 98% of potential neurotherapeutics unable to pass through. As a result, delivering sufficient drug concentrations to the brain remains a critical hurdle in AD management. Nanotechnology has opened up promising possibilities for drug delivery to the central nervous system. Nanoparticles (NPs) are particularly effective due to their small size, customizable surfaces, and potential for targeted delivery, making them an excellent solution for overcoming the BBB. Various nanocarriers, such as liposomes, polymeric nanoparticles, metallic nanoparticles, solid lipid nanoparticles (SLNs), micelles, and dendrimers, have been developed to enhance drug transport across the BBB, improving drug solubility, stability, bioavailability, and pharmacokinetics. Furthermore, functionalizing nanoparticles with ligands that target specific receptors on the BBB (e.g., transferrin, insulin, LDL receptors) enables more precise delivery via active targeting and transcytosis. Recent advancements also focus on green-synthesized nanoparticles and carriers loaded with natural compounds, which present environmentally friendly, biocompatible, and less toxic alternatives to traditional methods. This review explores recent progress in nanoparticle-based approaches for crossing the BBB and treating Alzheimer’s disease. It examines different types of nanoparticles, mechanisms for crossing the BBB, drug delivery methods, safety considerations, and future directions, with the goal of demonstrating how nanomedicine could transform AD treatment.

2. Pathophysiology of Alzheimer’s Disease

Alzheimer's disease (AD) is a complex neurodegenerative condition, primarily affecting older adults. Its progression is characterized by gradual cognitive decline, memory loss, changes in behavior, and ultimately, the loss of independence. At the molecular level, several interconnected pathological processes contribute to the onset and advancement of the disease, with the most prominent being:

2.1 Amyloid-β (Aβ) Plaques

One of the earliest and most extensively studied features of AD is the accumulation of amyloid-β (Aβ) peptides, which result from the abnormal cleavage of amyloid precursor protein (APP) by β- and γ-secretases. Particularly, Aβ42 peptides are prone to aggregation, forming insoluble extracellular plaques that interfere with neuronal communication and induce neuroinflammatory responses.

• Oligomeric forms of Aβ are considered highly neurotoxic and are associated with:
• Synaptic dysfunction

• Impaired neurotransmission

• Oxidative stress induction

• Activation of microglia and chronic neuroinflammation

2.2 Neurofibrillary Tangles (NFTs)

The second major pathological feature of AD is the formation of neurofibrillary tangles inside neurons, composed of hyperphosphorylated tau protein. Tau, a protein that stabilizes microtubules in neurons, becomes abnormally phosphorylated in AD, causing it to detach from microtubules, aggregate into twisted filaments, and form NFTs. This leads to neuronal damage and cell death.

2.3 Oxidative Stress and Mitochondrial Dysfunction

Oxidative stress and mitochondrial dysfunction are critical contributors to AD progression. The accumulation of Aβ and tau hyperphosphorylation intensify oxidative damage, resulting in lipid peroxidation, DNA damage, and protein oxidation. This oxidative imbalance disrupts cellular functions and accelerates neurodegeneration.

2.4 Neuroinflammation

Microglia, the brain's resident immune cells, become persistently activated in AD, releasing inflammatory cytokines such as TNF-α, IL-1β, and IL-6. This ongoing neuroinflammatory response exacerbates Aβ accumulation and tau pathology, creating a feedback loop that accelerates disease progression.

2.5 Cholinergic Deficits

AD is also marked by the loss of cholinergic neurons in the basal forebrain, leading to a significant reduction in acetylcholine (ACh) levels. This reduction is closely linked to impaired learning and memory, which is why cholinesterase inhibitors (e.g., donepezil, rivastigmine) are commonly used for symptomatic management.

2.6 Blood–Brain Barrier (BBB) Dysfunction

Recent studies suggest that the blood-brain barrier (BBB) is compromised in AD. A dysfunctional BBB impedes the clearance of Aβ, allows immune cells to infiltrate the brain, and contributes to neuroinflammation, further damaging neurons and complicating the delivery of drugs to the central nervous system (CNS). These overlapping pathological mechanisms highlight the need for therapeutic strategies that target multiple pathways and are capable of penetrating the brain. Nanoparticles, which can bypass or interact with the BBB to deliver drugs directly to the affected areas, present a promising approach to effectively addressing these pathological features.

Table 1. Key Pathological Mechanisms in Alzheimer’s Disease

3. The Blood–Brain Barrier and Its Role in Drug Delivery Challenges

The blood-brain barrier (BBB) is a dynamic, highly selective structure that safeguards the brain from potentially harmful substances in the bloodstream while preserving the homeostasis required for proper neural function. Despite its crucial protective role, the BBB presents a significant challenge to the delivery of therapeutic agents aimed at treating central nervous system (CNS) disorders, including Alzheimer’s disease (AD).

3.1 Structure and Function of the BBB

The BBB consists mainly of:

• Endothelial cells connected by tight junctions, which restrict the movement of molecules between cells.
• Pericytes, which help regulate vascular stability and permeability.

• Astrocytic end-feet, forming part of the neurovascular unit.

• A basement membrane, providing structural integrity. Together, these elements create a tightly controlled interface that selectively allows the passage of essential nutrients (e.g., glucose, amino acids) while blocking the entry of harmful substances such as pathogens, toxins, and most large or water-soluble molecules.

3.2 Drug Delivery Limitations Imposed by the BBB

More than 98% of small-molecule drugs and nearly all larger therapeutic agents (e.g., peptides, proteins, antibodies, nucleic acids) cannot cross the BBB at therapeutic concentrations. Key limitations include:

• Efflux transporters (e.g., P-glycoprotein) that actively pump drugs out of the brain.
• Tight junctions that prevent the passive diffusion of molecules.

• Enzymatic breakdown of drugs before or during their transit across the BBB.

• The absence of receptor-mediated uptake for many therapeutic agents. These challenges significantly reduce the effectiveness of traditional AD treatments and impede the development of new drug candidates that are unable to reach their intended targets in the brain.

3.3 BBB Dysfunction in Alzheimer’s Disease

Emerging research indicates that the BBB is often compromised in AD due to:

• Chronic neuroinflammation

• Vascular damage induced by Aβ accumulation
• Age-related changes in endothelial function
This dysfunction worsens disease progression by impairing the clearance of Aβ, allowing neurotoxic substances to enter the brain, and amplifying inflammatory responses.

3.4 The Need for Novel Delivery Strategies

Given these challenges, there is an urgent need for new drug delivery methods capable of bypassing or penetrating the BBB. Nanotechnology presents several promising solutions, including:
• Enhanced targeting of the brain through receptor-ligand interactions.

• Protection of drugs from degradation during transit.

• Controlled, sustained release of therapeutic agents.
• The potential for dual diagnostic and therapeutic functions (theranostics).

4. Nanoparticles as Vehicles to Cross the Blood–Brain Barrier

Nanoparticles (NPs) have transformed drug delivery systems by allowing therapeutic agents to cross the blood-brain barrier (BBB) through targeted and controlled approaches. Due to their distinctive physicochemical properties—such as their small size, adjustable surface charge, and capacity to carry both hydrophilic and hydrophobic drugs—NPs are well-suited for treating neurological disorders like Alzheimer’s disease (AD). This section discusses the various types of nanoparticles used, their mechanisms for penetrating the BBB, and their potential applications in AD treatment.

4.1 Advantages of Nanoparticles in Brain Drug Delivery

Nanoparticles offer several advantages for targeting the central nervous system (CNS):

• Small size (typically <200 nm): Enables NPs to diffuse through or undergo transcytosis across tight junctions in the BBB.

• Surface functionalization: Allows the attachment of targeting ligands (e.g., transferrin, lactoferrin, peptides) to enhance brain-specific delivery.

• Drug protection: Encapsulates drugs, shielding them from enzymatic degradation during transit.

• Controlled release: Provides sustained and localized drug delivery at the target site.

• Multifunctionality: Facilitates both diagnostic imaging and therapeutic applications within a single platform ("theranostics").

4.2 Mechanisms of BBB Penetration by Nanoparticles

Nanoparticles can cross the BBB via several pathways:

4.3 Types of Nanoparticles Used in Alzheimer’s Therapy

4.4 Functionalization for Targeted Delivery

Surface modification plays a crucial role in improving the ability of nanoparticles to cross the BBB and target specific areas:

• Ligand targeting: This involves attaching antibodies, peptides (e.g., RVG, TGN), or vitamins (e.g., folate) to nanoparticles for enhanced specificity.

• PEGylation: This modification extends the nanoparticles' circulation time in the body and helps prevent rapid clearance.

• Dual-functional systems: These systems combine targeting agents with imaging agents, enabling theranostic applications (both therapy and diagnostics in one platform). Nanoparticles have shown great potential in preclinical studies for improving brain drug delivery. Their ongoing development and refinement may help overcome many of the current challenges faced by existing AD treatments.

5. Specific Applications of Nanoparticles in Alzheimer’s Disease Treatment

Nanoparticles are designed not only to cross the blood-brain barrier (BBB) but also to interact with Alzheimer’s disease (AD) pathology at various levels. Their versatility allows them to carry drugs, natural compounds, imaging agents, and even genetic materials, making them powerful tools for both therapeutic and diagnostic (theranostic) applications. This section discusses how nanoparticles have been specifically utilized to target key AD-related mechanisms, such as amyloid-beta aggregation, tau pathology, oxidative stress, inflammation, and cholinergic dysfunction.

5.1 Targeting Amyloid-β Aggregation
The amyloid cascade hypothesis plays a central role in the pathogenesis of AD. Several nanoparticle systems have been developed to either reduce amyloid-beta (Aβ) accumulation or promote its clearance:

• Gold nanoparticles functionalized with peptides can bind to Aβ and prevent its aggregation.

• Selenium nanoparticles (SeNPs) aid in clearing Aβ and provide antioxidant effects.

• Polymeric nanoparticles loaded with Aβ-targeting antibodies or β-secretase inhibitors (BACE1 inhibitors) enhance targeted delivery of drugs to amyloid plaques.

5.2 Inhibiting Tau Hyperphosphorylation

Tau pathology, although less focused on than Aβ, is also a critical target for therapy:

• Dendrimers and polymeric nanoparticles have been used to deliver kinase inhibitors that help reduce tau hyperphosphorylation.

• PLGA-based nanoparticles deliver small molecules that prevent tau aggregation and promote microtubule stability.

5.3 Combating Oxidative Stress

Oxidative stress is both a trigger and a result of AD pathology. Nanoparticles loaded with antioxidants offer neuroprotective benefits:

• Curcumin-loaded liposomes and polymeric nanoparticles scavenge reactive oxygen species (ROS).
• Green-synthesized metal nanoparticles (e.g., silver, zinc oxide) exhibit both antioxidant and anti-amyloidogenic properties.

• Selenium and cerium oxide nanoparticles neutralize ROS and enhance mitochondrial function.

5.4 Modulating Neuroinflammation

Chronic activation of microglia leads to persistent neuroinflammation:

• Chitosan and PEGylated nanoparticles have been developed to deliver anti-inflammatory agents like NSAIDs, siRNA, or dexamethasone across the BBB.
• Natural anti-inflammatory compounds, such as resveratrol encapsulated in lipid-based nanoparticles, help reduce microglial activation and cytokine release.

5.5 Enhancing Cholinergic Function

Approved AD drugs, such as donepezil, rivastigmine, and galantamine, have limited ability to cross the BBB:

• Solid lipid nanoparticles (SLNs) and liposomes have been used to encapsulate donepezil, improving its delivery to cholinergic neurons in the cortex and hippocampus.

• SLNs modified with ApoE or transferrin ligands enhance the brain uptake of acetylcholinesterase inhibitors (AChEIs).

5.6 Natural Compound Delivery

Natural phytochemicals (e.g., curcumin, resveratrol, quercetin) possess neuroprotective effects but have poor solubility and BBB permeability:

• Nanocarriers significantly improve the bioavailability and targeting of these compounds.
• These systems have shown promise in reducing Aβ and tau toxicity, as well as oxidative and inflammatory responses.

5.7 Theranostic Applications

Nanoparticles can be engineered to serve dual diagnostic and therapeutic functions:

• Superparamagnetic iron oxide nanoparticles (SPIONs) conjugated with Aβ antibodies are used for MRI-based detection.

• Quantum dots and fluorescent-labeled nanoparticles enable early-stage AD imaging while simultaneously delivering therapeutic agents.

Nanoparticles provide a multifaceted approach to treating AD by targeting various pathological mechanisms. Their continued development holds the potential to offer more effective, targeted, and minimally invasive treatment options.

Table 2. Summary of Nanoparticle Applications in Alzheimer's Disease Therapy

6. Toxicity, Safety, and Regulatory Challenges in Nanoparticle-Based Alzheimer’s Therapy

Nanoparticle (NP)-based drug delivery systems hold great promise for Alzheimer’s disease (AD) treatment, but their clinical application is still hindered by concerns regarding toxicity, safety, and regulatory hurdles. It is essential that nanocarriers are biocompatible, non-immunogenic, and safely degradable in the body before they can be widely used in human therapies.

6.1 Toxicity and Biocompatibility Concerns

Nanoparticles interact with biological systems in complex ways that can sometimes result in unintended toxic effects. Major concerns include:

• Accumulation and persistence: Non-degradable nanoparticles may accumulate in organs such as the liver, spleen, and brain, leading to long-term toxicity.

• Oxidative stress: Some metal-based nanoparticles (e.g., silver, iron oxide) may produce reactive oxygen species (ROS), which can damage cells and organelles.

• Immune responses: Nanoparticle surface properties could trigger immune activation or allergic reactions, particularly with repeated use.

• Neurotoxicity: Poorly designed nanoparticles might interfere with neuronal function, potentially worsening AD symptoms.

Preclinical toxicity testing is crucial and should focus on:

• Hemocompatibility

• Inflammation markers

• BBB integrity

• Behavioral and neurocognitive effects in animal models

6.2 Green-Synthesized Nanoparticles: A Safer Alternative
Recent research has explored green synthesis methods using plant extracts and biocompatible materials to reduce toxicity:

• These methods avoid the harsh chemicals commonly used in traditional synthesis.

• They show reduced immunogenicity and improved biodegradability.

• They maintain or even enhance therapeutic efficacy in targeting Aβ and alleviating oxidative stress.
• These environmentally friendly techniques offer a more sustainable and safer path to clinical application, particularly for chronic diseases like AD.

6.3 Regulatory Barriers

The regulatory landscape for nanoparticle-based therapies is complex and evolving. Key challenges include:

• Standardization issues: There is a lack of consistent methods for characterizing nanoparticle properties, such as size, charge, drug loading, and release profiles.

• Reproducibility and scalability: Lab-scale formulations often fail to meet industrial-scale requirements for Good Manufacturing Practices (GMP).

• Long-term safety data: There is limited clinical data on the long-term effects of nanoparticles, particularly in elderly patients with comorbid conditions.

• Approval pathways: Current drug approval processes are not fully prepared to evaluate hybrid materials (e.g., combinations of drugs, imaging agents, and carriers). Regulatory agencies like the FDA and EMA are beginning to issue guidance for nanomedicines, but a unified global regulatory framework is needed to accelerate development.

6.4 Strategies to Overcome Challenges
To improve safety and regulatory compliance, the following strategies are recommended:

• Use biodegradable polymers (e.g., PLGA, chitosan).

• Optimize surface modifications to reduce immunogenicity.

• Conduct comprehensive in vivo toxicity studies, including cognitive and behavioral assessments.
• Engage with regulatory agencies early to design adaptive trials and identify accelerated approval pathways.

Despite these challenges, ongoing innovation in nanoparticle design, synthesis, and testing protocols is steadily advancing their safe and effective use in Alzheimer’s therapy.

Table 3. Toxicity and Safety Considerations for Nanoparticles in Alzheimer’s Disease Therapy