M. J. College, Bhilai, Chhattisgarh 490023
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory impairment, and the accumulation of amyloid-? (A?) plaques and neurofibrillary tangles. Despite extensive research, ctive therapeutic strategies remain limited, largely due to challenges such as the blood-brain barrier (BBB), poor bioavailability of drugs, and nonspecific systemic distribution. In recent years, nanotechnology has emerged as a transformative approach in AD therapy by enabling targeted delivery, enhanced drug stability, and improved therapeutic efficacy. This systematic review explores the latest advancements in nanotechnological interventions for AD treatment, highlighting key nanosystems such as polymeric nanoparticles, liposomes, solid lipid nanoparticles, dendrimers, nanoemulsions, and inorganic nanocarriers. These nanoscale platforms have demonstrated potential in facilitating BBB translocation, reducing amyloid aggregation, enabling sustained drug release, and providing multifunctional capabilities such as imaging and diagnostics alongside therapy. We critically analyze preclinical and clinical evidence on nanocarrier-mediated delivery of conventional anti-AD drugs (e.g., acetylcholinesterase inhibitors, memantine), gene therapies (siRNA, antisense oligonucleotides), and novel therapeutic agents targeting oxidative stress and neuroinflammation. Additionally, the review addresses the challenges and safety concerns associated with nanomedicine, including cytotoxicity, long-term accumulation, immunogenicity, and issues related to large-scale manufacturing and regulatory approval. Finally, we discuss future perspectives, emphasizing the need for standardized characterization of nanomaterials, translational research bridging bench to bedside, and personalized nano-therapeutic strategies. Overall, nanotechnology offers promising avenues to overcome current limitations in AD treatment and paves the way toward innovative, precise, and effective therapeutic solutions for this debilitating disease
Alzheimer’s disease (AD) is a major and growing neurodegenerative disorder, significantly impairing memory, cognition, and daily functioning [1]. Alzheimer’s disease (AD) is an irreversible neurodegenerative disorder, in which there is a progressive deterioration of intellectual and social functions, memory loss, personality changes and inability for self-care, and has become the fourth leading cause of death in developed countries. Pathogenesis of AD, there is a progressive deposition of β-amyloid (Aβ)- peptide in the hippocampal and cerebral cortical regions. This deposition is associated with the presence of neurofibrillary tangles (NFTs) and senile plaques. The senile plaques deposited between the neurons consist mainly protein β amyloid. Neurofibrillary tangles deposited inside the neurons fabricated from Tau protein. Diagnosing Alzheimer's requires careful medical evaluation thorough medical history, mental status testing, physical and neurological examination tests (such as blood tests and brain imaging), two classes of medications approved to treat AD. Cholinesterase inhibitors: Donepezil, Rivastigmine, Galantamine, NMDA receptor antagonists: Memantine[2].Emerging treatments for AD include drugs that target beta-amyloid and tau protein, stem cell-based therapies, non-invasive brain stimulation techniques, and dietary and lifestyle interventions [3].Worldwide, around 50 million people have dementia, and 50–70% of cases are attributed to AD [4]. Both the prevalence and incidence of AD increase with age. Globally, the population aged 65 years or older is expected to increase from 9.3% in 2020 to around 16.0% in 2050 [5]. In the United States, the prevalence of AD is approximately 3% in people aged 65–74, 17% in people aged 75–84, and 32% in people aged 85 or older [5]. The incidence of AD doubles every 10 years in those aged older than 60 [6]. Currently, about 5.8 million American adults suffer from AD, and the number is predicted to reach nearly 14 million by 2050 [7].
2.1. Overview of Alzheimer's Disease
Alzheimer’s disease (AD) is the most common cause of dementia and a progressive neurodegenerative disorder primarily affecting older adults. It leads to a gradual decline in memory, executive function, and daily living abilities, ultimately resulting in loss of independence and death. AD imposes a growing global health burden due to aging populations worldwide [8].Pathologically, AD is marked by two hallmark lesions in the brain: extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. Accumulation of Aβ peptides disrupts synaptic signaling and triggers a cascade of neurotoxic events, while tau pathology leads to microtubule destabilization and neuronal degeneration. In addition to these classical features, neuroinflammation, oxidative stress, mitochondrial dysfunction, synaptic loss, and vascular abnormalities play crucial roles in disease progression. Consequently, AD is now recognized as a multifactorial disorder rather than a disease driven by a single pathological mechanism [9].The etiology of AD involves a complex interplay of genetic, environmental, and lifestyle factors. Mutations in genes such as APP, PSEN1, and PSEN2 are associated with rare early-onset familial AD, whereas the APOE ε4 allele is the strongest genetic risk factor for late-onset sporadic AD. Aging remains the most significant risk factor, along with metabolic disorders, cardiovascular disease, and lifestyle factors [10].
2.2 Global Prevalence and Clinical Burden-
Alzheimer’s disease (AD), the most common form of dementia, constitutes a major and rapidly growing global health challenge that disproportionately affects older adults. Worldwide prevalence estimates indicate that tens of millions of individuals are living with AD and related dementias, with numbers rising sharply due to population aging and increased life expectancy. In 2019, an estimated ~51.6 million people globally were affected by AD and other dementias, with considerable regional variation in age-standardized prevalence rates. East Asia and high-income regions reported some of the highest prevalence figures, while lower rates were observed in regions such as South Asia and Western Sub-Saharan Africa [11].Long-term epidemiological studies show dramatic increases in disease burden over recent decades. Between 1990 and 2019, the global prevalence of AD and other dementias increased by more than 160 %, while incidence and associated mortality similarly escalated, reflecting demographic shifts and expanding elderly populations. Women generally exhibit a higher overall prevalence, largely attributable to longer life expectancy [12].
2.3. Limitations of conventional Therapies:
Despite decades of research and clinical use, conventional pharmacological therapies for Alzheimer’s disease (AD)—primarily cholinesterase inhibitors (ChEIs) such as donepezil, galantamine, and rivastigmine, and the NMDA receptor antagonist memantine—have substantial limitations that constrain their clinical utility and long-term effectiveness [13].
Firstly, these medications are fundamentally symptomatic in nature. ChEIs aim to enhance cholinergic neurotransmission, and memantine modulates glutamatergic excitotoxicity, but neither alters the underlying neurodegenerative processes, such as amyloid-β aggregation or tau hyperphosphorylation driving AD pathology. As a result, the benefits on cognition and function are modest and short-lived, typically slowing decline temporarily without changing disease progression [14].
Secondly, clinical efficacy varies widely among individuals. Many patients demonstrate limited or no meaningful cognitive improvement, and therapeutic responses tend to diminish as AD advances. Placebo arms in some long-term analyses even show comparable outcomes to certain drug regimens, underscoring the marginal effect sizes observed in clinical practice [15].
Thirdly, tolerability and adverse effects present challenges. ChEIs are commonly associated with gastrointestinal and autonomic side effects (e.g., nausea, diarrhea, dizziness), which contribute to reduced adherence and discontinuation. Although memantine is generally better tolerated, it can cause dizziness, headache, and somnolence [16].
3. PATHOPHYSIOLOGY OF ALZHEIMER'S DISEASE:
With pathophysiology of AD, debate goes back to the Alzheimer's time 1907 when he observed the neuropathological features of the disease i.e. amyloidal plaques and hyperphosphorylated NFTs. Several hypotheses have been put forward on the basis of the various causative factors in order to explain this multifactorial disorder [17]. Such as the cholinergic hypothesis, Aβ hypothesis, tau hypothesis and inflammation hypothesis [18].
3.1. Amyloid β plaque Formation:
Although the precise cause of Alzheimer's disease is not known, the β?amyloid peptide chains of 40–42 amino acids are suspected to contribute to the disease. The β?amyloid precursor protein is found on many types of cell membranes, and the action of secretases (β and γ) on this precursor protein normally releases the β?amyloids at a high rate into the plasma and the cerebrospinal fluid. However, the concentrations of the β?amyloids in the plasma and the spinal fluid vary considerably between laboratories. The β?amyloids adsorb in the nanomolar concentration range to receptors on neuronal and glial cells. The β?amyloids are internalized, become folded in the β?folded or β?pleated shape, and then stack on each other to form long fibrils and aggregates known as plaques. The β?amyloids likely act as monomers, dimers, or multimers on cell membranes to interfere with neurotransmission and memory before the plaques build up. Treatment strategies include inhibitors of β? and γ?secretase, as well as drugs and physiological compounds to prevent aggregation of the amyloids. Several immune approaches and a cholesterol?lowering strategy are also being tested to remove the β?amyloids [19].
3.2. Tau protein Hyper phosphorylation:
Alzheimer’s disease (AD) is the leading cause of dementia in elderly people. Amyloid beta (Aβ) deposits and neurofibrillary tangles are the major pathological features in an Alzheimer’s brain. These proteins are highly expressed in nerve cells and found in most tissues. Tau primarily provides stabilization to microtubules in the part of axons and dendrites. However, tau in a pathological state becomes hyperphosphorylated, causing tau dysfunction and leading to synaptic impairment and degeneration of neurons. This article presents a summary of the role of tau, phosphorylated tau (p-tau) in AD, and other tauopathies. Tauopathies, including Pick’s disease, frontotemporal dementia, corticobasal degeneration, Alzheimer’s disease, argyrophilic grain disease, progressive supranuclear palsy, and Huntington’s disease, are the result of misprocessing and accumulation of tau within the neuronal and glial cells. This article also focuses on current research on the post-translational modifications and genetics of tau, tau pathology, the role of tau in tauopathies and the development of new drugs targeting p-tau, and the therapeutics for treating and possibly preventing tauopathies [20].
3.3. Neuro-inflammation and Oxidative Stress:
Oxidative stress was also noted to modify the inflammatory response. Even though oxidative stress and neuroinflammation are two totally different pathological events, they are linked and affect one another. Nonetheless, there are still several mechanisms that need to be understood regarding the onset and the progress of neurodegenerative diseases in order to develop efficient therapies. As antioxidants are a means to alter oxidative stress and slow down the symptoms of these neurodegenerative diseases [21].
4. CHALLENGES IN ALZHEIMER'S TREATMENT:
Alzheimer's disease (AD) is the most prevalent, progressive and multifaceted neurodegenerative disorder associated with cognition, memory and behavioural impairments. There is no approved diagnosis or cure for AD, and it affects both developed and developing countries and causes a significant social and economic burden. Extracellular senile plaques of amyloid beta (Aβ) and intracellular neurofibrillary tangles of phosphorylated Tau (pTau) in the brain are considered to be the pathophysiological hallmarks of AD. In an attempt to explain the complexity and multifactorial nature of AD, various hypotheses (Aβ aggregation, Tau aggregation, metal dyshomeostasis, oxidative stress, cholinergic dysfunction, inflammation and downregulation of autophagy) based on pathophysiological changes that occur during the onset and progression of AD have been proposed. The complex and multifaceted pathophysiological nature of AD has hampered the identification and validation of effective biomarkers for early diagnosis and the development of disease-modifying therapies. Nevertheless, the amyloid hypothesis is the most widely accepted and is closely correlated with disease symptoms of AD that encompass all the disease hypotheses. Therefore, amyloid plaques are ideal biomarkers for the development of an early diagnosis of AD [22].
4.1. Blood-Brain-Barrier (BBB):
The blood-brain barrier (BBB) is a complex and unique semi-permeable membrane that serves as a protective structure to maintain homeostasis within the brain. However, it presents a significant challenge for the delivery of therapeutics into the brain [23].Lack of progress in treatment of AD is due to dual problems, both related to the blood–brain barrier (BBB). First, 98% of small molecule drugs do not cross the BBB, and ~100% of biologic drugs do not cross the BBB, so BBB drug delivery technology is needed in AD drug development. Second, the pharmaceutical industry has not developed BBB drug delivery technology, which would enable industry to invent new therapeutics for AD that actually penetrate into brain parenchyma from blood. In 2020, less than 1% of all AD drug development projects use a BBB drug delivery technology. The pathogenesis of AD involves chronic neuro-inflammation, the progressive deposition of insoluble amyloid-beta or tau aggregates, and neural degeneration. New drugs that both attack these multiple sites in AD, and that have been coupled with BBB drug delivery technology, can lead to new and effective treatments of this serious disorder [24].However, drugs may enter into CSF, but not cross the BBB. This is because there are two barriers in the brain.These are the brain capillary endothelial wall, which forms the BBB, and the choroid plexus, which forms the blood–CSF barrier [25].
4.2. Poor Drug Bioavailability:
Drug bioavailability measurements allow for the assessment of the absorption efficiency of a drug, including its absolute and relative bioavailability, the time to reach maximum concentration, and the area under the concentration–time curve [26]. Absolute bioavailability is defined as a measurement that determines the percentage of the active substance entering the bloodstream after administration of a drug when the reference standard is an intravenous dose. It expresses the efficiency of the absorption of the active substance by the body. It is usually less than 100%, since not all of the active substance is absorbed in the gastrointestinal tract [27]. The variety of factors affecting bioavailability is large. Interactions with other drugs, gastric pH levels, intestinal flora, and individual genetic differences in patients can alter drug bioavailability [28].
4.3. Systemic Side-Effect of Current Drugs:
Medications currently utilized for the treatment of AD include the acetylcholinesterase inhibitors (AChEIs, i.e., donepezil, rivastigmine, galantamine), and the N-methyl-d-aspartate receptor (NDMAR) antagonist, memantine. However, these medications provide only mild to moderate symptomatic benefit without altering underlying disease processes. The AChEIs inhibit the breakdown of acetylcholine which enhances cholinergic neurotransmission, and thus many of the adverse effects associated with the AChEIs are due to cholinergic effects. Memantine blocks NMDARs which is thought to reduce glutamate-induced excitotoxicity. Many of the adverse effects of memantine occur due to alterations in glutamatergic neurotransmission as well as through indirect or off-target effects on other neurotransmitter systems [29].
5. INTRODUCTION TO NANOTECHNOLOGY IN DRUG DELIVERY:
Nanotechnology has extensive application as nanomedicine in the medical field. Some nanoparticles have possible applications in novel diagnostic instruments, imagery and methodologies, targeted medicinal products, pharmaceutical products, biomedical implants, and tissue engineering. Today treatments of high toxicity can be administered with improved safety using nanotechnology, such as chemotherapeutic cancer drugs [30].The area of nanotechnology develops nanoscale-sized materials that consist of natural, synthetic/semisynthetic polymers, lipids, or metallic materials. Nanoparticles [NPS] can be used in targeted drug delivery to improve the bioavailability, biodistribution, and accumulation of therapeutics, preferentially in the targeted diseased area, acting as stability enhancers. These colloidal systems can deliver drugs to target sites to improve therapeutic efficiency, reduce toxicity, and reduce side effects, protecting the drug from biological degradation, achieving temporal and spatial control of therapeutics in the specific location of a disease [31].
5.1 Concept and principles of Nanotechnology:
The use of large sized materials in drug delivery raises several challenges, including in vivo stability, poor bioavailability/solubility/absorption, and issues with target-specific delivery, in addition to the side effects of the delivered drugs. Therefore, using new drug delivery systems for targeting drugs to a specific area in the body could be an opportunity to solve these critical issues [32]. Nanotechnology, based on the utilization of nanoparticles, has revolutionized drug delivery techniques, offering groundbreaking methods for managing and diagnosing intricate ailments over the past four decades [33]. In recent years nanotechnology has proven that nanoparticles acquire a great development in medical applications. Its combination with therapeutic drugs overcomes the limitations of free therapeutics. Further, these systems can deliver drug to specific tissues and provide controlled release therapy. This targeted and sustained drug delivery decreases the drug related toxicity and increases patient’s compliance with less frequent dosing. Recently, there are several outstanding applications of nanomedicine in the treatment of various chronic diseases [34].
5.2 Advantages of Nanotechnology in CNS Disorders:
Approximately 6.8 million people die annually because of problems related to the central nervous system (CNS), and out of them, approximately 1 million people are affected by neurodegenerative diseases that include Alzheimer’s disease, multiple sclerosis, epilepsy, and Parkinson’s disease. CNS problems are a primary concern because of the complexity of the brain. There are various drugs available to treat CNS disorders and overcome problems with toxicity, specificity, and delivery. Barriers like the blood–brain barrier (BBB) are a challenge, as they do not allow therapeutic drugs to cross and reach their target. Researchers have been searching for ways to allow drugs to pass through the BBB and reach the target sites. These problems highlight the need of nanotechnology to alter or manipulate various processes at the cellular level to achieve the desired attributes [35].
The drugs can also be nano-engineered to be delivered across the blood-brain barrier and perform specific functions. Therefore, this chapter tends to deliberate current understanding and recent findings on existing drug delivery routes and platforms using nanotechnological interventions. The chapter discusses challenges with nanomedicines developed for NDs and suggests personalized therapeutics as a solution [36].
Nanotechnology has the potential to improve treatment and diagnostic techniques for CNS disorders and facilitate effective drug transfer. With the aid of nanoengineering, drugs could be modified to perform functions like transference across the BBB, altering signaling pathways, targeting specific cells, effective gene transfer, and promoting regeneration and preservation of nerve cells [37].
These nano-based drugs have the ability to increase the therapeutic effect, reduce toxicity, exhibit good stability, targeted delivery, and drug loading capacity [38].
The nanocarriers have simplified the targeted delivery of therapeutics into the brain by surpassing the BBB and actively inhibiting the disease progression of CNS disorders [39].
Nanotechnology is an emerging field that is useful for various purposes. Numerous neurological disorders, such as Parkinson's disease (PD), Alzheimer's disease (AD), stroke, brain tumors, multiple sclerosis (MS), and epilepsy, are among the world's leading causes of death and disability today [40].
6. NANOCARRIERS OF ALZHEIMER'S DISEASE THERAPY:
Over the past few years, researchers have also explored how nanomaterials might be used in precision medicine [41]. As the only available treatment for AD cannot cross the BBB, it is limited to relieving symptoms. The numerous advantages of nanotechnology-based therapy suggest that this limitation may eventually be overcome [42]. Nanocarriers are used to treat various neurological disorders, including Alzheimer’s disease and brain cancer [43].
6.1 Polymeric Nanoparticles:
One of the major challenges in AD therapy is the restricted delivery of therapeutic agents across the blood–brain barrier (BBB). Polymeric nanoparticles (PNPs) have emerged as a promising nanocarrier system to overcome these limitations and enhance drug delivery to the central nervous system [44].Polymeric nanoparticles are colloidal systems generally ranging from 10–1000 nm, composed of biodegradable and biocompatible polymers such as poly(lactic-co-glycolic acid) (PLGA), chitosan, polycaprolactone (PCL), and polyethylene glycol (PEG). These systems can encapsulate hydrophilic and lipophilic drugs, protect them from degradation, provide sustained release, and improve bioavailability [45].Surface modification of polymeric nanoparticles with targeting ligands such as transferrin, lactoferrin, apolipoprotein E, or PEG enhances BBB penetration via receptor-mediated transcytosis. Functionalized polymeric systems have demonstrated improved accumulation in brain tissue and reduced systemic toxicity [46]. In addition to drug delivery, polymeric nanoparticles may exert neuroprotective effects by reducing oxidative stress, modulating neuroinflammation, and inhibiting Aβ aggregation. Chitosan-based nanoparticles, for instance, have shown improved mucoadhesion and suitability for intranasal delivery, offering a non-invasive nose-to-brain route [47].
6.2. Liposomes:
One of the primary obstacles in AD pharmacotherapy is the limited permeability of therapeutic agents across the blood–brain barrier (BBB). Liposomes have emerged as a promising nanocarrier system capable of enhancing drug delivery to the brain while minimizing systemic adverse effects [48].Liposomes are spherical vesicular structures composed of one or more phospholipid bilayers surrounding an aqueous core. Due to their amphiphilic nature, liposomes can encapsulate both hydrophilic drugs (within the aqueous compartment) and lipophilic drugs (within the lipid bilayer). Their biocompatibility, structural similarity to biological membranes, and capacity for surface modification make them suitable for central nervous system (CNS) drug delivery [49]. Liposomal formulations have been explored for delivering cholinesterase inhibitors, antioxidants, anti-amyloid agents, and natural compounds such as curcumin and resveratrol. Encapsulation within liposomes enhances drug stability, prolongs circulation time, and improves brain accumulation. For instance, liposomal curcumin has demonstrated improved bioavailability and enhanced inhibition of Aβ aggregation compared to free curcumin. Similarly, liposome-based delivery of donepezil and rivastigmine has shown improved pharmacokinetic profiles and reduced peripheral side effects [50].
6.2 Solid-Lipid Nanoparticles:
Effective pharmacological management of AD remains limited due to poor drug permeability across the blood–brain barrier (BBB), rapid systemic metabolism, and peripheral adverse effects. Solid lipid nanoparticles (SLNs) have emerged as a promising nanocarrier platform to address these therapeutic challenges [51].Solid lipid nanoparticles are submicron colloidal carriers typically ranging from 50–1000 nm, composed of physiologically compatible solid lipids stabilized by surfactants. Unlike traditional lipid emulsions, SLNs utilize lipids that remain solid at both room and body temperature, providing enhanced physical stability and controlled drug release. Their lipidic nature improves biocompatibility, reduces toxicity, and enhances interaction with biological membranes, making them suitable for central nervous system (CNS) drug delivery [52]. In AD therapy, SLNs have been investigated for encapsulating cholinesterase inhibitors, antioxidants, anti-inflammatory agents, and natural compounds such as curcumin, resveratrol, and quercetin. Drug incorporation into SLNs enhances solubility, protects labile molecules from degradation, and improves pharmacokinetic profiles. For example, SLN-based formulations of donepezil and rivastigmine have demonstrated prolonged systemic circulation and improved brain targeting compared to conventional oral formulations. Similarly, curcumin-loaded SLNs have shown enhanced bioavailability and increased inhibitory effects on Aβ aggregation in experimental models [53].
6.4 Dendrimers:
Dendrimers have emerged as a promising nanotechnological platform due to their unique structural architecture and multifunctional capabilities [54]. Dendrimers are highly branched, tree-like macromolecules composed of a central core, repetitive interior branching units, and multiple surface functional groups. Their well-defined nanoscale size (typically 1–15 nm), monodispersity, and high surface functionality allow precise drug loading and surface modification. Commonly studied dendrimers in biomedical applications include poly(amidoamine) (PAMAM), poly(propylene imine) (PPI), and carbosilane dendrimers [55]. Several studies have demonstrated that dendrimers can cross or interact with the BBB, especially when surface-modified with polyethylene glycol (PEG), transferrin, lactoferrin, or specific peptides that facilitate receptor-mediated transcytosis. Hydroxyl-terminated PAMAM dendrimers, for example, have shown selective accumulation in activated microglial cells in neuroinflammatory conditions, suggesting their potential for targeted drug delivery in AD [56].
6.5. Nano-emulsions:
Nano emulsion based drug delivery systems have emerged as a promising strategy to enhance brain targeting, improve bioavailability, and reduce systemic adverse effects [57].Nanoemulsions are thermodynamically or kinetically stable colloidal dispersions consisting of oil, water, surfactant, and often co-surfactant, with droplet sizes typically ranging from 20 to 200 nm. Due to their small droplet size and large surface area, nanoemulsions enhance solubilization of lipophilic drugs and facilitate improved absorption. Their physicochemical properties can be tailored to optimize drug loading, stability, and controlled release [58].nanoemulsions have been investigated for delivering antioxidants, anti-amyloid agents, cholinesterase inhibitors, and phytoconstituents such as curcumin, resveratrol, and quercetin. Encapsulation of such compounds in oil-in-water nano emulsions enhances their chemical stability and improves pharmacokinetic profiles. For example, curcumin nano emulsions have demonstrated enhanced brain uptake and greater inhibition of Aβ aggregation compared to free drug formulations in preclinical models. Similarly, intranasal nano emulsion systems containing donepezil or rivastigmine have shown improved nose-to-brain transport, thereby by passing first-pass metabolism and enhancing central nervous system (CNS) availability [59].
6.6 Metallic Nanoparticles:
Metallic nanoparticles, typically ranging from 1–100 nm in size, exhibit high surface-to-volume ratios, tunable optical properties, and the ability to be functionalized with biological ligands, making them promising candidates for applications in neurodegenerative disorders [60]. Among various metallic systems, gold nanoparticles (AuNPs), silver nanoparticles (AgNPs), iron oxide nanoparticles (IONPs), and cerium oxide nanoparticles (nanoceria) have been extensively studied in AD research. Gold nanoparticles possess favorable biocompatibility and ease of surface modification. Functionalized AuNPs have demonstrated the ability to bind amyloid-β peptides, potentially inhibiting fibril formation and destabilizing pre-formed aggregates. Additionally, AuNPs conjugated with targeting ligands such as peptides or antibodies can enhance selective delivery to neuronal tissue [61]. Metallic nanoparticles can be engineered with polymeric or lipid coatings to enhance biocompatibility, prolong circulation time, and reduce cytotoxicity. Surface functionalization with polyethylene glycol (PEG) or specific targeting moieties improves BBB penetration and reduces nonspecific interactions. However, despite promising preclinical outcomes, issues such as long-term accumulation, metal ion release, oxidative toxicity, and safety concerns remain significant barriers to clinical translation [62].
7. MECHANISM OF NANOPARTICLES TRANSPORT ACROSS BBB:
The blood–brain barrier (BBB) is a highly selective and dynamic interface that regulates molecular exchange between the systemic circulation and the central nervous system (CNS). It is primarily composed of brain microvascular endothelial cells interconnected by tight junctions, supported by pericytes, astrocytic end-feet, and a basement membrane. While the BBB maintains neural homeostasis, it significantly restricts the entry of most therapeutic agents, particularly large and hydrophilic molecules. Nanoparticle-based drug delivery systems have been extensively investigated to overcome this barrier through multiple transport mechanisms [63].
7.1 Receptor Mediated Transport:
Receptor-mediated transport plays a central role in regulating molecular exchange across the blood–brain barrier (BBB) and has become a key strategy for targeted drug delivery in Alzheimer’s disease (AD). The BBB consists of tightly joined endothelial cells that restrict passive diffusion of most therapeutic agents into the brain. However, certain endogenous molecules such as transferrin, insulin, and lipoproteins enter the brain via receptor-mediated transcytosis (RMT), a highly selective vesicular transport process. Nanocarrier systems designed to exploit these physiological pathways offer a promising approach to enhance central nervous system (CNS) drug delivery in AD [64]. In receptor-mediated transcytosis, a ligand present on the nanoparticle surface binds specifically to receptors expressed on brain endothelial cells. This interaction triggers endocytosis, followed by intracellular vesicular trafficking and subsequent exocytosis on the abluminal side of the BBB, allowing the therapeutic payload to reach the brain parenchyma. Among the various receptors investigated, the transferrin receptor (TfR) is one of the most extensively studied targets due to its abundant expression on BBB endothelial cells. Nanoparticles conjugated with transferrin or anti-TfR antibodies have demonstrated enhanced brain uptake in experimental AD models [65].
7.2 Adsorptive Mediated Transport
Adsorptive-mediated transport (AMT) is a non-specific, charge-dependent mechanism that facilitates the translocation of macromolecules and nanocarriers across the blood–brain barrier (BBB). In Alzheimer’s disease (AD), where efficient central nervous system (CNS) drug delivery remains a major therapeutic challenge, AMT has emerged as a promising strategy to enhance nanoparticle uptake into brain tissue [66].The BBB is formed by tightly connected endothelial cells that restrict paracellular diffusion. While receptor-mediated transcytosis depends on ligand–receptor specificity, adsorptive-mediated l relies primarily on electrostatic interactions. The luminal surface of brain endothelial cells carries a net negative charge due to glycoproteins and proteoglycans. Positively charged (cationic) es can interact electrostatically with this negatively charged membrane surface, initiating endocytosis and subsequent vesicular transport across endothelial cells [67].AMT has also been explored for delivering peptides, proteins, and gene-based therapeutics relevant to Alzheimer’s pathology. Cationized antibodies targeting amyloid-β (Aβ) peptides have demonstrated improved brain entry through adsorptive interactions. Similarly, positively charged liposomes and dendrimers have exhibited enhanced uptake in experimental CNS models [68].
7.3 Carrier Mediated Transport
Carrier-mediated transport (CMT) represents one of the principal physiological mechanisms governing solute exchange across the BBB. This process involves solute carrier (SLC) transporter proteins expressed on brain capillary endothelial cells that facilitate the movement of essential nutrients such as glucose, amino acids, nucleosides, and monocarboxylates along concentration gradients. Unlike passive diffusion, CMT is substrate-specific and depends on conformational changes in transporter proteins to shuttle molecules across cellular membranes [69].Among the key transporters exploited for therapeutic targeting are glucose transporter 1 (GLUT1) and L-type amino acid transporter 1 (LAT1). GLUT1 is abundantly expressed at the BBB and ensures continuous glucose supply to meet cerebral metabolic demands, while LAT1 mediates the uptake of large neutral amino acids. Because of their high expression and substrate specificity, these transporters have been investigated as potential gateways for drug or prodrug entry into the brain [70].In Alzheimer’s disease, alterations in transporter expression have been reported, particularly involving glucose transport systems, which may contribute to impaired cerebral metabolism observed in AD patients. Such dysregulation not only exacerbates neuronal vulnerability but may also influence the efficiency of transporter-targeted drug delivery systems. Understanding disease-associated changes in BBB transporter profiles is therefore critical for optimizing CMT-based therapeutic strategies [71]. To exploit CMT for therapeutic purposes, drug molecules can be chemically modified into prodrugs that structurally resemble endogenous transporter substrates. By mimicking glucose or amino acid motifs, these modified compounds can engage specific SLC transporters and gain facilitated access to the brain. This substrate-mimicry approach enhances brain uptake without disrupting BBB integrity [72].
8. NANOTECHNOLOGY-BASED DRUG DELIVERY OF ANTI-ALZHEIMER'S AGENT:
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by amyloid-β (Aβ) plaque accumulation, tau hyperphosphorylation, synaptic dysfunction, and cognitive decline. Although several anti-Alzheimer’s agents such as acetylcholinesterase inhibitors and NMDA receptor antagonists are clinically available, their therapeutic efficacy is limited by poor blood–brain barrier (BBB) permeability, rapid systemic clearance, and dose-related adverse effects. The BBB remains the principal obstacle to effective central nervous system (CNS) drug delivery in AD therapy [73].Nanotechnology has emerged as a promising strategy to enhance brain delivery of anti-Alzheimer’s agents by improving drug stability, bioavailability, and targeted transport across the BBB. Nanocarriers ranging from 1–200 nm can encapsulate therapeutic molecules, protect them from enzymatic degradation, and facilitate controlled or sustained release. Their surfaces can be engineered with ligands that interact with BBB transport systems, thereby enhancing brain accumulation of drugs [74].Lipid-based nanocarriers, including liposomes and solid lipid nanoparticles (SLNs), are widely investigated due to their biocompatibility and ability to carry both hydrophilic and lipophilic drugs. Surface modification with targeting ligands such as transferrin, glucose, or peptides enables receptor- or carrier-mediated transport across the BBB. These systems have been explored for delivering donepezil, rivastigmine, and other cholinergic agents with improved brain bioavailability and reduced systemic toxicity [75].Polymeric nanoparticles, particularly those composed of biodegradable polymers such as poly(lactic-co-glycolic acid) (PLGA), provide enhanced stability and controlled drug release profiles. These carriers can be functionalized to target amyloid plaques or tau pathology, enabling site-specific drug accumulation. Additionally, polymeric systems support co-delivery of multiple therapeutic agents, addressing the multifactorial mechanisms underlying AD pathology [76].Dendrimers represent another nanoplatform characterized by highly branched architecture and modifiable surface groups, allowing high drug-loading capacity and precise targeting. In experimental AD models, dendrimer-based systems have demonstrated potential in reducing neuroinflammation and enhancing penetration across the BBB. Their tunable structure makes them suitable for conjugation with anti-amyloid or antioxidant agents [77].Despite encouraging preclinical findings, translation into clinical practice requires careful evaluation of long-term safety, nanoparticle biodistribution, immunogenicity, and large-scale manufacturing feasibility. Furthermore, BBB alterations in AD patients may influence nanocarrier transport efficiency, necessitating disease-specific optimization strategies [78].
8.1 Nanocarriers for Cholinesterase Inhibitors:
Cholinesterase inhibitors (ChEIs) such as donepezil, rivastigmine, and galantamine remain first-line symptomatic treatments for Alzheimer’s disease (AD). These agents enhance cholinergic neurotransmission by inhibiting acetylcholinesterase (AChE) and, in some cases, butyrylcholinesterase (BuChE). However, their clinical efficacy is limited by poor blood–brain barrier (BBB) penetration, short half-life, peripheral side effects, and dose-dependent gastrointestinal toxicity. Consequently, nanotechnology-based carrier systems have been explored to improve brain targeting and reduce systemic exposure [79].Alzheimer’s disease is associated with progressive degeneration of cholinergic neurons and depletion of acetylcholine in cortical and hippocampal regions [80].Clinically approved cholinesterase inhibitors such as Donepezil, Rivastigmine, and Galantamine provide symptomatic relief by inhibiting acetylcholinesterase and butyrylcholinesterase enzymes [81].Nanocarrier-based delivery systems have therefore been investigated to enhance central nervous system bioavailability while minimizing systemic toxicity [82].
Lipid-based nanocarriers, including solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs), have shown significant potential in improving the delivery of cholinesterase inhibitors to the brain [83].These carriers increase drug solubility, protect against enzymatic degradation, and provide sustained drug release [84].Intranasal administration of donepezil-loaded lipid nanoparticles has demonstrated higher brain drug concentrations compared to conventional oral formulations in experimental models, indicating effective nose-to-brain transport and partial bypass of the BBB [85].
Polymeric nanoparticles formulated from biodegradable polymers such as PLGA, chitosan, and PEGylated copolymers offer controlled drug release, improved stability, and enhanced pharmacokinetic profiles[86].
Studies involving rivastigmine- and galantamine-loaded polymeric nanoparticles have reported prolonged brain residence time and improved cognitive outcomes in preclinical models [87].Surface modification with targeting ligands further facilitates receptor-mediated transport across the BBB, promoting selective neuronal drug accumulation [88].
Biomimetic nanocarriers, including extracellular vesicles and exosome-derived systems, represent an advanced strategy for CNS-targeted therapy [89].Due to their endogenous origin and membrane protein composition, these carriers exhibit enhanced biocompatibility and efficient BBB traversal [90].Comparative investigations have demonstrated superior acetylcholinesterase inhibition and improved behavioral performance when donepezil was delivered using extracellular vesicles compared with conventional polymeric nanoparticles in animal studies [91].
Despite promising preclinical findings, translation of nanocarrier-based cholinesterase inhibitor delivery into clinical practice remains limited,Challenges include large-scale reproducible manufacturing, long-term toxicity evaluation, regulatory standardization, and cost-effectiveness assessment [92].Continued research focusing on safety profiling and clinical validation is essential before widespread therapeutic implementation can be achieved [93].
8.2 Nanoparticle Delivery of Antioxidants:
Oxidative stress plays a central role in the pathogenesis of Alzheimer’s disease (AD), contributing to neuronal damage, mitochondrial dysfunction, lipid peroxidation, and amyloid-β toxicity [94]. Excess generation of reactive oxygen species (ROS) disrupts cellular homeostasis and accelerates neurodegeneration.Although antioxidants such as Curcumin, Resveratrol, Quercetin, and Vitamin E demonstrate neuroprotective potential, their clinical application is limited due to poor aqueous solubility, low bioavailability, rapid metabolism, and restricted blood–brain barrier (BBB) penetration [95].Nanoparticle-based delivery systems have therefore been explored to enhance brain targeting and therapeutic efficacy of antioxidant compounds [96].
Polymeric nanoparticles formulated using biodegradable polymers such as PLGA, chitosan, and PEGylated systems have been widely studied for antioxidant delivery [97]. Encapsulation of curcumin or resveratrol within polymeric nanoparticles improves chemical stability, prolongs systemic circulation, and enables sustained drug release [98]. Preclinical studies indicate that nano-encapsulated antioxidants reduce amyloid aggregation, attenuate oxidative stress markers, and improve cognitive performance in AD animal models compared with free compounds [99].
Metallic and inorganic nanoparticles possessing intrinsic antioxidant properties have also been investigated. Cerium oxide nanoparticles exhibit enzyme-mimetic activity by scavenging superoxide radicals and hydrogen peroxide, thereby reducing oxidative damage in neuronal tissues [100] .Similarly, selenium nanoparticles demonstrate protective effects by modulating redox balance and inhibiting amyloid aggregation. These nanozymes offer dual functionality as both carriers and active antioxidant agents [101].
8.3 Nano-Based Delivery of Peptides and Protein
Therapeutic peptides and proteins have gained considerable attention in Alzheimer’s disease (AD) due to their high specificity and ability to modulate pathological pathways such as amyloid-β aggregation, tau hyperphosphorylation, neuroinflammation, and synaptic dysfunction. Examples include anti-amyloid monoclonal antibodies, neurotrophic factors, and enzyme-based therapeutics [102].However, clinical application is significantly restricted by poor stability in systemic circulation, rapid enzymatic degradation, immunogenicity, short half-life, and limited penetration across the blood–brain barrier (BBB) [103].Nanotechnology-based delivery systems have been investigated to protect these biomolecules and enhance their transport into the central nervous system [104].
Polymeric nanoparticles prepared from biodegradable materials such as PLGA, chitosan, and PEGylated polymers provide structural protection to encapsulated peptides and proteins. These carriers reduce proteolytic degradation, enable sustained release, and improve pharmacokinetic behavior [105]. Surface modification with targeting ligands such as transferrin, lactoferrin, or apolipoprotein mimetics promotes receptor-mediated transcytosis across the BBB [106]. Preclinical investigations demonstrate that nanoparticle-encapsulated neuroprotective peptides exhibit improved brain accumulation and enhanced therapeutic outcomes compared with free peptides [107].
Biomimetic nanocarriers such as exosomes and cell membrane-coated nanoparticles represent advanced strategies for peptide and protein transport. Exosomes possess inherent BBB-crossing capability and low immunogenicity, making them attractive vehicles for delivering therapeutic proteins and gene-editing components [108].Experimental studies indicate that exosome-mediated delivery of neprilysin and other amyloid-degrading enzymes reduces amyloid plaque burden and oxidative stress in AD models [109].
8.4 Nano-Based Delivery of Peptides and Protein
Peptide- and protein-based therapeutics are increasingly explored in Alzheimer’s disease (AD) because of their high specificity toward pathological targets such as amyloid-β (Aβ), tau protein, and neuroinflammatory mediators. Examples include monoclonal antibodies against Aβ, neurotrophic factors like brain-derived neurotrophic factor (BDNF), and amyloid-degrading enzymes [110]. Despite their therapeutic promise, these biomolecules face major limitations including enzymatic degradation, short systemic half-life, immunogenicity, and restricted transport across the blood–brain barrier (BBB) [111].Nanotechnology-based delivery systems have been developed to enhance their stability, protect bioactivity, and facilitate targeted brain delivery [112].
Polymeric nanoparticles composed of biodegradable materials such as PLGA, chitosan, and PEGylated polymers provide structural protection for encapsulated peptides and proteins. These systems reduce premature degradation and allow controlled or sustained release profiles [113].Surface functionalization with ligands targeting BBB receptors—such as transferrin or lactoferrin—enhances receptor-mediated transcytosis and improves central nervous system accumulation [114]. Experimental studies have demonstrated that nano-encapsulated neuroprotective peptides exhibit improved pharmacokinetics and greater neuroprotective efficacy compared with free molecules [115].
Lipid-based nanocarriers, including liposomes and solid lipid nanoparticles, are particularly suitable for delivering hydrophilic proteins and antibodies due to their biocompatibility and membrane-mimicking properties [116].Liposomal encapsulation has been shown to prolong systemic circulation time and reduce immunogenic reactionsreactions [117].Intranasal administration of protein-loaded lipid nanoparticles further enhances direct nose-to-brain transport, partially bypassing the BBB and reducing peripheral exposure [118].
Biomimetic nanocarriers such as exosomes and cell membrane-coated nanoparticles represent advanced delivery platforms for peptides and proteins. Exosomes possess intrinsic BBB-crossing capability and low toxicity, making them attractive for transporting therapeutic enzymes and antibodies [119]. Studies have shown that exosome-mediated delivery of amyloid-degrading enzymes can reduce plaque burden and oxidative stress in AD models, highlighting their translational potential [120].
Although nano-based delivery systems significantly improve stability, targeting, and therapeutic performance of peptide and protein drugs, several challenges remain. These include maintaining protein bioactivity during formulation, large-scale reproducible manufacturing, long-term toxicity assessment, and regulatory approval complexities [121]. Future research should focus on optimizing formulation parameters and conducting well-designed clinical studies to establish safety and efficacy in humans [122].
8.5 Gene and Si-RNA Delivery Using Nanotechnology
Gene therapy and small interfering RNA (siRNA) approaches are emerging strategies for modifying the underlying molecular mechanisms of Alzheimer’s disease (AD). These techniques aim to regulate or silence genes involved in amyloid-β production, tau hyperphosphorylation, neuroinflammation, and oxidative stress [123]. Targets such as BACE1 (β-secretase), tau protein, and pro-inflammatory mediators have been investigated for RNA interference–based modulation [124]. However, naked nucleic acids are rapidly degraded in circulation, exhibit poor cellular uptake, and cannot efficiently cross the blood–brain barrier (BBB). Nanotechnology-based delivery systems have therefore been developed to protect genetic material and facilitate targeted brain delivery [125].
Polymeric nanoparticles formulated from biodegradable polymers such as PLGA, chitosan, polyethyleneimine (PEI), and PEGylated copolymers are widely used for gene and siRNA delivery. These nanocarriers condense nucleic acids into stable complexes, protect them from nuclease degradation, and promote endosomal escape after cellular uptake [126]. Surface functionalization with ligands targeting BBB receptors—such as transferrin or apolipoprotein E mimetic peptides—enhances receptor-mediated transcytosis and improves brain accumulation [127]. Experimental models have demonstrated that nanoparticle-mediated delivery of BACE1-siRNA reduces amyloid burden and improves cognitive performance [128].
Dendrimers and inorganic nanoparticles have also been explored as gene delivery vehicles. Polyamidoamine (PAMAM) dendrimers provide high nucleic acid loading capacity and controlled surface modification for targeted delivery [129]. Additionally, gold nanoparticles and magnetic nanoparticles have been investigated for gene transport and imaging-guided therapy. These multifunctional platforms combine diagnostic and therapeutic capabilities, offering theranostic potential in neurodegenerative diseases [130].
Despite promising preclinical outcomes, several challenges limit clinical translation of nano-enabled gene therapy in AD [131]. Concerns include long-term safety, immune responses, off-target gene silencing, scalability of production, and regulatory approval pathways. Future research should focus on optimizing carrier biocompatibility, improving targeting specificity, and conducting rigorous clinical trials to establish therapeutic efficacy and safety [132].
9. SAFETY, TOXICITY AND REGULATORY CHALLENGES
Although nanotechnology-based drug delivery systems offer significant advantages for improving brain targeting in Alzheimer’s disease (AD), concerns regarding safety and toxicity remain critical barriers to clinical translation [133]. Nanoparticles can interact with biological systems in complex ways depending on their size, surface charge, composition, and route of administration [134]. Potential risks include oxidative stress induction, inflammation, complement activation, and unintended accumulation in organs such as the liver, spleen, or brain. Therefore, comprehensive toxicological profiling is essential before clinical application [135].
One major concern in neurotherapeutic nanomedicine is neurotoxicity. Due to their small size and ability to cross the blood–brain barrier (BBB), nanoparticles may accumulate in neural tissue and potentially interfere with neuronal signaling or mitochondrial function[136]. Metallic nanoparticles, particularly silver and some forms of metal oxides, have been reported to induce reactive oxygen species generation and cellular stress responses [137].Even biodegradable polymeric nanoparticles require careful evaluation to assess long-term degradation products and their potential impact on brain homeostasis [138].
Immunogenicity and systemic toxicity are additional challenges. Surface characteristics of nanoparticles can trigger immune responses, complement activation, or hypersensitivity reactions [139]. Cationic carriers used for gene or siRNA delivery may cause membrane disruption and cytotoxicity [140]. Moreover, repeated dosing strategies—often required for chronic conditions like AD—raise concerns regarding bioaccumulation and chronic inflammation. Standardized in vitro and in vivo toxicity assessment models are therefore necessary to predict long-term safety [141].
From a regulatory perspective, nanomedicines face unique challenges due to their complex physicochemical properties and multifunctional design. Regulatory agencies such as the U.S. Food and Drug Administration and the European Medicines Agency require detailed characterization of particle size distribution, surface chemistry, stability, manufacturing reproducibility, and biodistribution [142]. However, harmonized global guidelines specifically tailored to nanotechnology-based products remain limited, creating uncertainty in approval pathways [143].
Manufacturing scalability and quality control also present obstacles. Ensuring batch-to-batch consistency, sterility, and stability during storage is more complex for nanoscale formulations compared to conventional pharmaceuticals [144]. Advanced analytical techniques are required to monitor critical quality attributes, including particle aggregation, encapsulation efficiency, and release kinetics . Addressing these challenges requires collaboration between researchers, industry stakeholders, and regulatory authorities to establish standardized evaluation frameworks [145].
9.1 Nanotoxicity and Biocompatibility Issues
Nanoparticles possess unique physicochemical properties such as small size, high surface area, and tunable surface charge, which enhance drug delivery efficiency but may also introduce safety concerns [146]. In Alzheimer’s disease (AD) therapy, the ability of nanoparticles to cross the blood–brain barrier (BBB) raises particular concerns regarding long-term accumulation and potential neurotoxicity [147]. Toxicological responses are influenced by particle composition, size distribution, surface functionalization, dose, and route of administration. Therefore, systematic evaluation of nanotoxicity is essential before clinical translation [148].
One major mechanism of nanoparticle-induced toxicity involves oxidative stress. Certain metallic and inorganic nanoparticles can generate reactive oxygen species (ROS), leading to lipid peroxidation, mitochondrial dysfunction, DNA damage, and activation of apoptotic pathways [149]. In neural tissue, excessive ROS production may aggravate neuroinflammation and synaptic dysfunction [150].Even polymeric nanoparticles, although generally considered safer, require assessment of degradation by-products and their long-term effects on neuronal homeostasis [151].
Neuroinflammation and immune activation are additional concerns. Nanoparticles may interact with microglia and astrocytes, triggering inflammatory cytokine release and complement activation [152]. Surface charge plays a critical role in immunogenicity; positively charged nanoparticles often exhibit higher cellular uptake but may cause membrane destabilization and cytotoxicity [153].Repeated administration, which is common in chronic diseases like AD, increases the risk of bioaccumulation and persistent inflammatory responses [154].
Biocompatibility depends largely on material selection and surface engineering strategies. Biodegradable polymers such as PLGA and naturally derived materials like chitosan are generally regarded as safer alternatives due to controlled degradation and minimal systemic toxicity [155]. Surface PEGylation can reduce protein adsorption and prolong circulation time, thereby minimizing immune recognition [156]. However, protein corona formation in biological fluids can alter nanoparticle behavior, affecting biodistribution, efficacy, and safety profiles [157].
Standardized evaluation methods for nanotoxicity remain a challenge. Conventional in vitro cytotoxicity assays may not accurately predict in vivo outcomes due to complex nanoparticle–biological interactions [158]. Advanced models, including 3D cell cultures, organ-on-chip systems, and long-term animal studies, are increasingly recommended to assess neurotoxicity and biocompatibility[159]. Harmonized regulatory frameworks are required to establish clear safety assessment guidelines for nanomedicine products intended for central nervous system applications [160].
10. RECENT ADVANCES & ONGOING RESEARCH:
Recent advances in Alzheimer’s disease (AD) research reflect a shift from the traditional amyloid-centric hypothesis toward a multifactorial disease model integrating amyloid-β aggregation, tau pathology, neuroinflammation, synaptic dysfunction, mitochondrial impairment, and vascular contributions [161]. Contemporary reviews emphasize that these interconnected pathological mechanisms interact over decades before clinical symptoms appear, highlighting the importance of early intervention strategies and multi-target therapeutic approaches rather than single-pathway modulation [162].
One of the most significant recent breakthroughs is the development of disease-modifying monoclonal antibodies targeting amyloid-β. Phase III clinical trials of lecanemab and donanemab demonstrated statistically significant slowing of cognitive decline in early Alzheimer’s disease, providing clinical validation that amyloid reduction can influence disease progression [163]. Although concerns remain regarding amyloid-related imaging abnormalities (ARIA) and cost-effectiveness, these therapies represent a milestone in translating mechanistic insights into clinical benefit [164].
Parallel research is increasingly focused on tau-targeted therapies, given the stronger correlation between tau pathology and cognitive impairment compared to amyloid burden [165]. Current strategies include anti-tau monoclonal antibodies, tau aggregation inhibitors, antisense oligonucleotides, and active immunotherapies. Ongoing clinical trials aim to determine whether early modulation of tau propagation can significantly alter disease trajectory [166].
Biomarker research has advanced substantially, enabling earlier and less invasive diagnosis. Blood-based biomarkers such as plasma phosphorylated tau (p-tau217, p-tau181), amyloid-β42/40 ratio, and neurofilament light chain (NfL) have demonstrated high diagnostic accuracy and strong concordance with cerebrospinal fluid and PET imaging findings [167]. These developments support a biological definition of AD and facilitate improved patient stratification in therapeutic trials [168].
Emerging evidence highlights neuroinflammation as a critical driver of disease progression rather than merely a secondary consequence of amyloid accumulation [169]. Microglial activation, complement pathway dysregulation, and pro-inflammatory cytokine release contribute to neuronal injury and synaptic loss. Genetic studies identifying variants in immune-related genes such as TREM2 further support the role of immune modulation as a promising therapeutic strategy [170].
Precision medicine and artificial intelligence (AI) approaches are increasingly being integrated into AD research [171]. Machine learning algorithms applied to multimodal datasets—including genetic information, neuroimaging, and biomarker profiles—are improving early diagnosis and prediction of disease progression. Such computational tools may enhance individualized therapeutic decision-making and optimize clinical trial design [172].
Current ongoing research is increasingly oriented toward combination therapies and multi-target-directed ligands (MTDLs) designed to simultaneously address cholinergic deficits, oxidative stress, amyloid aggregation, and tau hyperphosphorylation [173]. This integrative strategy aligns with the multifactorial pathogenesis of AD and may offer synergistic benefits compared to single-target approaches. Continued translational research is essential to validate long-term efficacy and safety in diverse patient populations [174].
11. FUTURE PROSPECTS OF NANOTECHNOLOGY IN ALZHEIMER'S DISEASE:
Nanotechnology offers promising future directions for Alzheimer’s disease (AD) by addressing key limitations of conventional therapies, especially drug delivery across the blood–brain barrier (BBB). Advanced nanocarrier systems such as polymeric nanoparticles, solid lipid nanoparticles, and dendrimers have shown potential to improve brain targeting, enhance therapeutic bioavailability, and reduce systemic toxicity. These engineered nanocarriers can be functionalized with ligands that facilitate receptor-mediated transport across the BBB, enabling efficient delivery of anti-amyloid, anti-tau, or neuroprotective agents directly to affected neuronal tissues [175].
Future research is likely to emphasize multifunctional nanosystems and theranostics, which combine diagnostic imaging and treatment within a single platform. These multifunctional nanoparticles can simultaneously detect pathological markers (such as amyloid-β or tau aggregates) and deliver therapeutic payloads, offering real-time monitoring of disease progression and treatment efficacy. Such integrated systems may significantly enhance early diagnosis and personalized therapy strategies, potentially transforming clinical management of AD [176].
Emerging material classes such as nanoenzymes and stimuli-responsive nanomaterials represent another frontier for future interventions in AD. Nanoenzymes—with enzyme-mimicking capabilities—can mitigate oxidative stress, a key pathological contributor in AD, by scavenging reactive oxygen species and protecting neurons from oxidative injury. Stimuli-responsive nanoparticles that release therapeutic agents in response to disease-specific triggers (e.g., pH changes or reactive oxygen levels) may further increase therapeutic precision and reduce off-target [177].
Integration of nanotechnology with novel therapeutic modalities such as phytochemical-based treatments and magneto-mechanical regulation may further expand future possibilities. Phytochemical nanocarriers can overcome limitations of natural compounds (poor CNS penetration and off-target effects) by enhancing their stability and brain delivery, while magneto-regulated strategies using magnetic nanoparticles and external fields may enable remote and precise control of therapeutic activity within the brain [178].
Despite these advances, clinical translation remains a key challenge. Issues such as large-scale manufacturing reproducibility, long-term biocompatibility, immunogenicity, and regulatory approval require focused research efforts. Future work must also explore the safety profiles of prolonged nanoparticle administration and address ethical considerations associated with nanomedicine interventions in vulnerable populations such as elderly patients [179].
Overall, continued innovation in nanoparticle design, combined with interdisciplinary research integrating nanotechnology, pharmacology, and neuroscience, will likely propel the next generation of AD diagnostics and therapeutics [180].
11. CONCLUSION
Nanotechnology has emerged as a transformative platform in the treatment of Alzheimer’s disease (AD), offering innovative solutions to long-standing challenges associated with conventional therapeutic strategies. By enabling targeted drug delivery across the blood–brain barrier, enhancing bioavailability of therapeutic agents, and minimizing systemic toxicity, nanoscale systems provide a strategic advantage over traditional formulations. Functionalized nanoparticles, lipid-based carriers, polymeric systems, dendrimers, and inorganic nanomaterials have demonstrated promising capabilities in delivering anti-amyloid, anti-tau, antioxidant, and gene-based therapies directly to affected neuronal tissues. (Singh et al., 2025; Liu et al., 2025)
Beyond drug delivery, nanotechnology also supports early diagnosis and disease monitoring through advanced nanosensors and multifunctional theranostic platforms. These integrated systems hold potential for simultaneous detection and treatment, paving the way for personalized and precision-based interventions in Alzheimer’s disease. Additionally, advances in stimuli-responsive nanocarriers, nanoenzymes, and gene-modulating nanoplatforms suggest that future therapies may not only alleviate symptoms but also modify underlying disease mechanisms. (Bi et al., 2024; Shen et al., 2023)
Despite encouraging preclinical findings, challenges related to long-term safety, large-scale manufacturing, regulatory approval, and clinical translation remain significant. Comprehensive toxicity evaluation, improved standardization of nanoparticle characterization, and interdisciplinary collaboration will be essential to bridge the gap between laboratory research and clinical application. In conclusion, while nanotechnology-based therapies for Alzheimer’s disease are still evolving, their capacity to enhance targeted delivery, enable multimodal treatment approaches, and support early diagnosis positions nanomedicine as a promising frontier in neurodegenerative disease management. Continued innovation and rigorous clinical validation are likely to determine its ultimate impact on improving patient outcomes in the coming years. (Hu et al., 2023; Tutubala et al., 2025).
REFERENCES
Artee Yadav, Himanshu Thakur, Rahul Singh, Parasmani Markam, Emerging Role of Nanotechnology in Treatment of Alzheimer's Disease - A Systemic Review, Int. J. of Pharm. Sci., 2026, Vol 4, Issue 5, 1796-1825. https://doi.org/10.5281/zenodo.20085493
10.5281/zenodo.20085493
