Advancements in the Application of Nanomedicine in Alzheimer’s Disease: A Therapeutic Perspective

Alzheimer’s disease (AD) is a progressive neurodegenerative disease that affects most people worldwide. AD is a complex central nervous system disorder. Several drugs have been designed to cure AD, but with low success rates. Because the blood–brain and blood–cerebrospinal fluid barriers are two barriers that protect the central nervous system, their presence has severely restricted the efficacy of many treatments that have been studied for AD diagnosis and/or therapy. The use of nanoparticles for the diagnosis and treatment of AD is the focus of an established and rapidly developing field of nanomedicine. Recent developments in nanomedicine have made it possible to effectively transport drugs to the brain. However, numerous obstacles remain to the successful use of nanomedicines in clinical settings for AD treatment. Furthermore, given the rapid advancement in nanomedicine therapeutics, better outcomes for patients with AD can be anticipated. This article provides an overview of recent developments in nanomedicine using different types of nanoparticles for the management and treatment of AD.


Introduction
Today, the world's foremost cause of death and infirmity is central nervous system; (CNS) disorders, mostly involving neurodegenerative diseases (ND), which cause great pain to patients and their relatives.NDs, including Alzheimer's disease (AD), Parkinson's disease (PD), epilepsy, dementia, Huntington's disease, amyotrophic lateral sclerosis, multiple sclerosis (MS), brain stroke, and injuries, are the most common CNS diseases [1,2].Gustavsson et al. (2022) projected that 416 million people globally fall into the AD continuum, which is significantly higher than the frequently reported estimate of 50 million individuals experiencing dementia [3].Neurofibrillary tangles (NFT) and amyloid beta (Aβ) plaques are signs of the disease.Although AD has well-known neural characteristics, its symptoms are momentarily alleviated by the available treatments [4].Many medicines licensed for the treatment of cognitive deficits are based on the manipulation of neurotransmitters or enzymes.However, difficulties related to poor drug solubility, low bioavailability, and inability to overcome barriers along the drug delivery route impede the development of new therapeutic options [5].Therefore, treatment technologies must overcome the obstacles posed by the blood-brain barrier (BBB).Only a few molecules can pass through this intricate and tightly controlled barrier, which examines the biochemical, physicochemical, and structural characteristics of neighboring molecules at the perimeter.Numerous nanotechnology-based platforms have been developed to improve therapeutic efficacy in the brain [6,7].These aided medication delivery techniques utilize advanced design principles and have several advantages over conventional techniques [8].For example, formulations are highly customizable to increase drug loading, targeting, and release efficacy, and nanoparticles (NPs) are often low-cost technologies that can be employed for noninvasive administration [9].These nanoscale structures make it easier for drugs to cross the BBB, enhancing their pharmacokinetics, pharmacodynamics, and bioavailability.Polymeric NPs, dendrimers, and lipid-based NPs are examples of such nanocarriers [10].This article aimed to gather relevant information concerning the barriers in drug design for AD and the clinical use of NPs in the development of a new formulation for AD treatment.We searched the PubMed, Google Scholar, and Scopus databases for review articles, research articles, studies on nanomedicine, and clinical trials relevant to the fields of nanomedicine-based treatments against AD.Moreover, this review provides a brief overview of AD, barriers to developing therapeutic agents, the role of NPs, and their clinical aspects.

Alzheimer's Disease
AD is a severe, fatal, progressive brain illness that impairs cognitive abilities [11].The two most popular theories for the pathogenesis of AD are the excess and aggregation of Aβ peptide in the form of plaques and microtubule-associated tau protein becoming abnormally hyperphosphorylated and forms NFT that accumulates in the brain of AD; however, synaptic disturbance for calcium influx, autophagy, microgliosis-astrogliosis, and neuron demyelination are considered major factors in AD pathophysiology (Figure 1).Recent research has shown that chronic oxidative stress (OS), mitochondrial dysfunction, hormone imbalance, inflammation, genetic components, or BBB dysfunction may also play crucial roles in the pathogenesis of AD [12,13].Food and Drug Administration-approved therapies for AD are currently available and are related primarily to two biochemical pathways involving the buildup of Aβ-peptide and NFT of p-tau protein.However, they have poor effectiveness in treating AD, demonstrating the necessity for other therapeutic strategies.Identifying additional molecular targets through discovering novel biomarkers may help the development of new treatments for AD [14].
Int. J. Mol.Sci.2023, 24, x FOR PEER REVIEW 2 of 33 that can be employed for non-invasive administration [9].These nanoscale structures make it easier for drugs to cross the BBB, enhancing their pharmacokinetics, pharmacodynamics, and bioavailability.Polymeric NPs, dendrimers, and lipid-based NPs are examples of such nanocarriers [10].This article aimed to gather relevant information concerning the barriers in drug design for AD and the clinical use of NPs in the development of a new formulation for AD treatment.We searched the PubMed, Google Scholar, and Scopus databases for review articles, research articles, studies on nanomedicine, and clinical trials relevant to the fields of nanomedicine-based treatments against AD.Moreover, this review provides a brief overview of AD, barriers to developing therapeutic agents, the role of NPs, and their clinical aspects.

Alzheimer's Disease
AD is a severe, fatal, progressive brain illness that impairs cognitive abilities [11].The two most popular theories for the pathogenesis of AD are the excess and aggregation of Aβ peptide in the form of plaques and microtubule-associated tau protein becoming abnormally hyperphosphorylated and forms NFT that accumulates in the brain of AD; however, synaptic disturbance for calcium influx, autophagy, microgliosis-astrogliosis, and neuron demyelination are considered major factors in AD pathophysiology (Figure 1).Recent research has shown that chronic oxidative stress (OS), mitochondrial dysfunction, hormone imbalance, inflammation, genetic components, or BBB dysfunction may also play crucial roles in the pathogenesis of AD [12,13].Food and Drug Administration-approved therapies for AD are currently available and are related primarily to two biochemical pathways involving the buildup of Aβ-peptide and NFT of p-tau protein.However, they have poor effectiveness in treating AD, demonstrating the necessity for other therapeutic strategies.Identifying additional molecular targets through discovering novel biomarkers may help the development of new treatments for AD [14].The emergence of intracellular NFT and the production of extracellular Aβ plaques in the brain are key indicators of AD onset [15,16].The histopathological characteristics are the loss of hippocampal neurons, synaptic degeneration, and aneuploidy.Additionally, early pathophysiological changes in AD have been linked to neuroinflammation, OS, mitochondrial dysfunction, and an injured brain lymphatic system [17,18].
AD is complicated by several variables, including genetic, environmental, health, and lifestyle factors.Obesity, hypertension, high cholesterol, and diabetes are only a few conditions that increase the risk of developing AD [19][20][21].
Researchers have studied many therapeutic targets.Among the therapeutic targets, common strategies include Aβ-based, tau protein-based, NFT-based, mitochondrial, OS, anti-inflammatory, and blood-brain receptor targeting (Table 1).The emergence of intracellular NFT and the production of extracellular Aβ plaques in the brain are key indicators of AD onset [15,16].The histopathological characteristics are the loss of hippocampal neurons, synaptic degeneration, and aneuploidy.Additionally, early pathophysiological changes in AD have been linked to neuroinflammation, OS, mitochondrial dysfunction, and an injured brain lymphatic system [17,18].
AD is complicated by several variables, including genetic, environmental, health, and lifestyle factors.Obesity, hypertension, high cholesterol, and diabetes are only a few conditions that increase the risk of developing AD [19][20][21].
Researchers have studied many therapeutic targets.Among the therapeutic targets, common strategies include Aβ-based, tau protein-based, NFT-based, mitochondrial, OS, anti-inflammatory, and blood-brain receptor targeting (Table 1).The emergence of intracellular NFT and the production of extracellular Aβ plaques in the brain are key indicators of AD onset [15,16].The histopathological characteristics are the loss of hippocampal neurons, synaptic degeneration, and aneuploidy.Additionally, early pathophysiological changes in AD have been linked to neuroinflammation, OS, mitochondrial dysfunction, and an injured brain lymphatic system [17,18].
AD is complicated by several variables, including genetic, environmental, health, and lifestyle factors.Obesity, hypertension, high cholesterol, and diabetes are only a few conditions that increase the risk of developing AD [19][20][21].
Researchers have studied many therapeutic targets.Among the therapeutic targets, common strategies include Aβ-based, tau protein-based, NFT-based, mitochondrial, OS, anti-inflammatory, and blood-brain receptor targeting (Table 1).

Challenges of Drug Designing for AD Treatment
The brain is regarded as the best-protected body organ.Several protective barriers surround the brain, including the skull, meninges, cerebrospinal fluid, and BBB.These elements contribute to the brain's defense against external and internal harm as well as helping it stay healthy.However, in a diseased state, these protective barriers make it more difficult for therapeutic drugs to reach the brain [58].The major barriers, including the BBB, blood-cerebrospinal fluid barrier (BCFB), and multidrug resistance proteins (MDRPs), are briefly discussed.

The Blood-Brain Barrier
The BBB is the principal barrier that prevents nanomedicines from entering the brain, limiting their ability to treat and diagnose AD.Therefore, nanomedicines should be intelligently developed to increase their capacity for brain accumulation [59,60].The BBB, which prevents many medications from entering the brain at adequate concentrations, is the main obstacle in treating neurological illnesses.Moreover, unintended adverse effects resulting from drug release from the carrier before it reaches the brain further complicate treatment efforts.The BBB comprises endothelial cells, basal membranes, pericytes, and astrocytes (Figure 2).Tight junctions provide unique characteristics to the BBB.Consequently, the BBB prevents the entry of medications that are effective in treating a variety of neurological illnesses.
the main obstacle in treating neurological illnesses.Moreover, unintended adverse effects resulting from drug release from the carrier before it reaches the brain further complicate treatment efforts.The BBB comprises endothelial cells, basal membranes, pericytes, and astrocytes (Figure 2).Tight junctions provide unique characteristics to the BBB.Consequently, the BBB prevents the entry of medications that are effective in treating a variety of neurological illnesses.Brain capillaries appear to have essentially no intercellular interstitial gaps.As a result, transit likely involves all cells.Consequently, lipid-soluble compounds can pass freely through all endothelial membranes and easily cross the BBB [61].Various different strategies are mentioned in recent studies, including direct injection, nose-to-brain route, the opening of BBB, inhibition of efflux transporters, and use of nanocarrier [62]; however, among these strategies, nanocarrier seems to be the most appropriate and result-oriented.Brain capillaries appear to have essentially no intercellular interstitial gaps.As a result, transit likely involves all cells.Consequently, lipid-soluble compounds can pass freely through all endothelial membranes and easily cross the BBB [61].Various different strategies are mentioned in recent studies, including direct injection, nose-to-brain route, the opening of BBB, inhibition of efflux transporters, and use of nanocarrier [62]; however, among these strategies, nanocarrier seems to be the most appropriate and result-oriented.
Using cutting-edge therapeutic nano-delivery devices may solve the problem of crossing the BBB [63][64][65][66][67].Because of their distinctive physicochemical features and capacity to penetrate the BBB, engineered NPs < 100 nm have multiple applications in resolving these biological and pharmacological problems [68].The ability of NP to cross the BBB increases the likelihood of early diagnosis and successful treatment of neurological diseases [69].However, six different access routes that could be used to cross the BBB are paracellular diffusion (hydrophilic molecule), transcellular diffusion, carrier-mediated transport, receptor-mediated transport, adsorptive-mediated transport, and cell-mediated transport [62].Paracellular transport is a passive transport process that results in the transport of substances across an epithelium.Tight junctions are the major rate-limiting pathway in the paracellular transport of large molecules across the epithelium [70].Large molecules such as polypeptides are generally excluded from paracellular diffusion due to their hydrophilicity and high molecular mass.Adsorption-mediated transcytosis has attracted much attention because of its potential for large-molecule drug delivery to the brain.Cationic albumin-mediated brain DDS is commonly used; however, coupling this component with NP DDS is proven to be successful in cross-BBB for CNS delivery.Polymeric NPs are commonly used for adsorption-mediated transcytosis [71].Immunocytes, neutrophils, and lymphocytes have a high degree of mobility, and they can cross various barriers to reach the target site and release their medication cargo.To enhance drug delivery, these cells can be loaded with nanocarriers such as polymeric NPs.In receptor-mediated DDS, transferrin receptors, low-density lipoprotein receptors, and insulin receptors are commonly used.A complex is formed between the desired drug and a receptor-targeting agent.This component is then linked or incorporated into the NPs [72].Transcellular diffusion of molecules is based on their solubility, their molecular mass, and charge [73].One important process for drug transportation over the BBB carrier-mediated transcytosis is used for the entrance of nutrition and energy intake into the brain cells.The benefits of carrier-mediated transport have been grafted onto nano DDSs using a technique that involves functionalizing the surface of the tiny molecules with certain ligands [74].Among these six pathways, except the cell-mediated pathway, other five pathways are commonly used in nanomedicine delivery that cross the BBB for AD management, as shown in Figure 3.

The Blood-Cerebrospinal Fluid Barrier
The BCFB, which is constructed by epithelial cells of the choroid plexus and systematically deals with drug compounds, is the next barrier to overcome after the BBB.The choroid plexus epithelium (CPE) is one of the most effective tissue types and is based on secretory systems that balance cellular transport mechanisms.This epithelial barrier divides the blood and CSF in a manner similar to that of the BBB.Cells near the CSF-facing surface had an adjacent CPE that was tightly preserved.The CPE comprises detoxifying enzymes and multi-specific efflux transport proteins that work together to block the entry of potentially deadly substances into the CNS.Several medication delivery strategies have been developed; most are suited to the BBB and target the microvascular endothelium [75,76].For the treatment of CNS disorders, targeting the BCFB, which is sculpted by the

The Blood-Cerebrospinal Fluid Barrier
The BCFB, which is constructed by epithelial cells of the choroid plexus and systematically deals with drug compounds, is the next barrier to overcome after the BBB.The choroid plexus epithelium (CPE) is one of the most effective tissue types and is based on secretory systems that balance cellular transport mechanisms.This epithelial barrier divides the blood and CSF in a manner similar to that of the BBB.Cells near the CSF-facing surface had an adjacent CPE that was tightly preserved.The CPE comprises detoxifying enzymes and multi-specific efflux transport proteins that work together to block the entry of poten-tially deadly substances into the CNS.Several medication delivery strategies have been developed; most are suited to the BBB and target the microvascular endothelium [75,76].For the treatment of CNS disorders, targeting the BCFB, which is sculpted by the choroid epithelium, is crucial, in addition to targeting the BBB [77].
In order to enhance the administration of CNS therapies and offer brain protection measures, the BCFB, a less well-studied brain barrier location than the BBB, may serve as a possible therapeutic target.Therefore, by conducting a preliminary evaluation of the anticipated physiochemical behavior of a drug against this barrier, the use of reliable and accurate in vitro models of the BCFB can reduce the time and effort spent on pointless or repetitive research efforts.The development of innovative CNS treatments and pharmacologically active candidates that take advantage of the choroid plexus epithelial cells' inherent transporting ability will be beneficial for developing CNS drug delivery strategies through the BCFB.There are still questions concerning the CP's suitability for this purpose despite the fact that it has not received much attention as a prospective route for medication delivery to the brain.By using the current in vitro BCFB models, preliminary mechanistic and transport experiments can be used to assess the efficiency of the design process and the rate of successful transport across this barrier.Protein receptors, solute carriers, and amino acid transporters are three key groups of possible transporters that could be targeted to facilitate medication delivery to the CNS across the BCFB [78].

Multidrug Resistance Proteins
The BBB is formed by endothelial cells within brain capillaries and this cerebral endothelial cells contain diverse metabolic enzymes, including cytochrome P450 enzymes, alkaline phosphatases, and glutathione transferases, as well as energy-dependent efflux transport proteins, such as P-glycoprotein (P-gp), breast cancer resistance protein (BCRP; ABCG2), and MDRPs, which are arranged asymmetrically and act as barrier [79][80][81].These MDR transporters, P-gp and BCRP, belong to the ATP-binding cassette (ABC) superfamily and prevent exposure of the brain to a large range of molecules [82]; this makes therapy unsuccessful by preventing some drugs from precisely achieving their intended therapeutic goals while also reducing drug buildup in the brain [83].Among these transporters, MDRP is a main barrier for drug distribution to the brain due to its concentrative efflux activity.Changes to the expression levels of MDRP possibly alter drug concentrations in brain and spinal cord tissues.An alternative approach could be used for drug delivery by inhibiting the expression and function of P-gp [84].Therefore, one of the current key issues in pharmaceutical research is the development of tools that allow for the efficient and effective delivery of medications into the CNS by the MDRP system [85].Simultaneously, there is a need to gain a better understanding of ABC transporter activity at the BBB and BCFB that could correctly predict the drug pharmacokinetics and pharmacodynamics in the CNS.
The major feature of AD, a multifactorial ND that primarily affects older people, is a progressive decline in cognition, emotion, language, and memory.Pharmaceutical medication formulations and cholinesterase inhibitors have been widely promoted as AD treatments because of their beneficial effects.To enhance patients' cognitive results, these drugs were eventually found to be unsuccessful in addressing the underlying causes of AD pathogenesis and instead focused only on symptoms [86,87].
Therefore, the market's current drug delivery technologies cannot offer sufficient cytoarchitectural recovery and interconnections, which are essential for real recovery in AD.The concepts and methods of nanotechnology mentioned in this review can also substantially eradicate AD.However, nanotechnology can overcome these limitations by developing novel carrier-based platforms focusing on the targeted selective release of pharmacological payloads with on-demand and controlled release kinetics and improved reach by altering or evading the BBB.Nanomaterials have been studied for administering anti-AD drugs in experimental models of AD.This review covers several synergistic strategies in depth, providing details on the symptoms, risk factors, treatment options, and function of nanocomposites in slowing the progression of AD [88].

Nanomedicine
Maintaining the bioavailability, pharmacodynamics, and pharmacokinetics of medications is crucial to exerting their full therapeutic effects.Therefore, the goal of integrating a drug into or onto a polymeric and/or lipid NP is to substantially increase the drug's therapeutic effect.The use of NPs in drug delivery is advantageous because they increase a drug's bioavailability by enhancing its aqueous solubility and lengthening its half-life, which, in turn, slows the pace of drug clearance and delivers the medication to its intended site of action [89][90][91].Furthermore, a wide range of NPs is used to treat AD [92]. Figure 4 shows the use of various NPs in the development of nanomedicines for the management and treatment of AD.Nanoliposome carriers are the most promising drug delivery methods because of their biocompatibility and high flexibility in delivering a variety of therapeutic compounds across the BBB and specifically targeting brain cells.Evidence demonstrates that PSLs can cross the BBB to enter the brain, where they interact with several types of neuronal cell receptors [93].

Metallic/Inorganic Nanoparticles
Metallic NPs have been extensively used in recent years for the diagnosis, imaging, and treatment of NDs.Metallic NPs commonly contain gold NPs (AuNP), silver (Ag) NPs, iron oxide (FeO) NPs, platinum (Pt) NPs, and ceria (Ce2O3) NPs.These NPs play a significant role as DDSs in brain-targeted therapies.Metallic NPs can be easily fabricated and functionalized by adding different functional groups, and their shapes and sizes can be modified [94].The conjugation of metallic NPs with drug molecules, antibodies, DNA/RNA, peptides, and aptamers has been extensively studied in recent years [95].Among the metallic NPs, AuNPs have been widely used in diagnosis and imaging, such as in DDS.
Because of their biocompatibility, fascinating optical features, surface functionalization, and non-immunological qualities, AuNPs have gained significant interest as novel platforms for catalysis, drug transport, and disease diagnosis and treatment.AuNPs have Nanoliposome carriers are the most promising drug delivery methods because of their biocompatibility and high flexibility in delivering a variety of therapeutic compounds across the BBB and specifically targeting brain cells.Evidence demonstrates that PSLs can cross the BBB to enter the brain, where they interact with several types of neuronal cell receptors [93].

Metallic/Inorganic Nanoparticles
Metallic NPs have been extensively used in recent years for the diagnosis, imaging, and treatment of NDs.Metallic NPs commonly contain gold NPs (AuNP), silver (Ag) NPs, iron oxide (FeO) NPs, platinum (Pt) NPs, and ceria (Ce 2 O 3 ) NPs.These NPs play a significant role as DDSs in brain-targeted therapies.Metallic NPs can be easily fabricated and functionalized by adding different functional groups, and their shapes and sizes can be modified [94].The conjugation of metallic NPs with drug molecules, antibodies, DNA/RNA, peptides, and aptamers has been extensively studied in recent years [95].
Among the metallic NPs, AuNPs have been widely used in diagnosis and imaging, such as in DDS.
Because of their biocompatibility, fascinating optical features, surface functionalization, and non-immunological qualities, AuNPs have gained significant interest as novel platforms for catalysis, drug transport, and disease diagnosis and treatment.AuNPs have also been developed to treat various CNS illnesses owing to their various dimensions, forms, and surface features [96].Numerous researchers have used AuNPs to develop therapeutic compounds for the treatment of AD.According to Shao et al. (2023), AuNPs have been used to modify Aβ fibrillation associated with AD in intracellular and extracellular areas [97].An aptamer-conjugated polydopamine-coated AuNP formulation was prepared to treat AD and tested on PC12 cells.The formulation inhibits the aggregation of the Aβ peptides and prevents Aβ-induced cell membrane damage [98].In 2015, Gao et al. designed an AuNPs-based formulation where AuNPs were conjugated with polyoxometalate as an Aβ inhibitor for AD treatment.The formulation effectively inhibits Aβ aggregation, dissociates Aβ fibrils, and reduces peroxidase activity and cytotoxicity.This success is attributed to the advantageous use of AuNPs as BBB-crossing carriers [99].In a recent study, AD model rats were treated with AuNPs conjugated with okadaic acid (OA).AuNPs were observed to maintain p-tau levels in the cortex and hippocampus; however, OA increased p-tau levels.Rats treated simultaneously with OA and AuNP showed high interleukin (IL)-1β and IL-4 levels in the hippocampus and cortex.AuNPs exhibit antioxidant properties and reduce OS in the brain [100].Sanati et al. studied the impact of AuNPs on Aβ-induced AD in experimental rats, finding that AuNPs may enhance learning and memory for spatial information, and the expression level of stromal interaction molecules was increased, leading to an improvement in neural survival [101].Studies have shown that AuNPs are multifunctional therapeutic agents for the treatment of AD.
Selenium nanoparticles (SeNPs) have received considerable attention because of their exceptionally low toxicity and antioxidative qualities.Selenium is a micronutrient crucial for preserving human health and lowering OS in the brain.Because of their outstanding neuroprotective properties, they have been implicated in the prevention of AD [102].Selenium-and sodium selenite-rich NPs have antioxidant qualities and are utilized to treat brain illnesses; they also enhance cognitive function in a size-dependent manner [103].Yin et al. conducted in vitro studies to examine the interactions between B6-SA-SeNPs and amyloid peptides as well as to assess the effectiveness of B6-SA-SeNPs when delivered to brain capillary endothelial cells.Because of their anti-amyloid, antioxidant, and high brain transport efficiency, the findings indicated that B6-SA-SeNPs could be a useful treatment for AD and a novel nanomedicine for disease modification in AD [102].
Neurotoxicity, DNA damage by inorganic NPs, and biochemical properties of the brain and iono-regulatory processes are the major challenges of this nanocarrier in AD therapeutics.

Carbon-Based Nanoparticles
A large category of carbon-based nanomaterials, known as "carbon dots" (CDs), are broadly divided into carbon nanodots, polymer dots, carbon nitride dots, and graphene quantum dots (QDs), which are used as DDSs for the treatment of NDs [104].Top-down and bottom-up strategies were used to synthesize CDs, and a range of reaction conditions and precursors were used.The successful penetration of the BBB by a variety of CDs and CD ligand conjugates indicates encouraging advancement in the use of CD-based DDS for the treatment of CNS disorders [105].
The development of CDs has resulted in numerous advancements in recent years, including the delivery of medications that can traverse the BBB [106][107][108].CDs are biocompatible and harmless because they do not contain metals.Owing to their abundance of surface functional groups, CDs can be conjugated to a variety of pharmacological compounds as nanocarriers through either covalent or noncovalent interactions.Most importantly, the combination of substantial surface diversity and small particle size simplifies the transfer of drugs across the BBB via active pathways.Additionally, the photoluminescence of CDs makes it simple to follow their in vivo movements in real time.With the help of these promising NPs, additional medications can now be transported to the brain, rendering the fight against AD and other NDs a new weapon [109].One published study demonstrated the significance of yellow-emissive CD (Y-CDs) in AD treatment.According to these results, Y-CD crosses the BBB, enters cells, and inhibits the overexpression of human amyloid precursor protein and Aβ [106].Another study also revealed the potential of CDs as a multifunctional β-sheet breaker and provided a promising anti-Aβ aggregation strategy for AD treatments [110].In 2022, Yan et al. developed multifunctional CD photosensitizer nanoassemblies to inhibit amyloid aggregates that could easily cross the BBB and prevent microbial growth after treatment [111].These recent studies demonstrate the potential significance of CD in CNS and its promising role as an inhibiting agent for the Aβ-related pathology of AD.Chung et al. fabricated targeting CDs that were red light-responsive and capable of suppressing Aβ aggregation and neurotoxicity in the brain of a patient with AD [112].
QDs are NPs with electronic and optical characteristics such as fluorescence and strong light emission.They possess distinct qualities, such as photostability, high quantum yield, high emission, and size tunability.The use of theranostic NPs in sensing, imaging, and medication delivery is currently receiving considerable attention.Additionally, QDs hold significant promise for the identification and management of several CNS disorders, including PD, AD, and MS.In several areas of life sciences, QDs are semiconductor nanocrystals with unique optical features, including high photochemical stability, extended wavelength, and long fluorescent half-life [113].Some varieties of conjugated QDs are suitable carriers and are valuable for traversing the BBB in a variety of applications, including accurate imaging and detection of brain illnesses.The primary factor for transferring across the BBB is the particle surface, not the NPs' size or chemo-electric charge [114].One study synthesized QDs from the extract of the flower of Clitoria ternatea and observed that the learning and memory capacity of treated rats improved in the radial arm and Morris water maze assays.These results also confirmed that QDs significantly inhibited AChE, increased the levels of glutathione and proteins, and decreased the levels of lipid peroxide and nitric oxide [115].In a study by Wang et al., a nanoformulation of graphene oxide (GO)-loaded dauricine was developed for the treatment of AD and was evaluated in an AD experimental model both in vivo and in vitro.The findings demonstrated that GO loaded with dauricine significantly decreased OS by increasing superoxide dismutase levels, lowering reactive oxygen species, and decreasing malondialdehyde levels in vitro.It also significantly improved cognitive memory impairment and brain glial cell activation in mice with Ab1-42-induced AD.Thus, GO-loaded dauricine has the potential to be a useful drug for the rapid treatment of AD.This study showed that GO loaded with dauricine protected against Ab1-42-induced oxidative damage and apoptosis in both AD models [116].
A recent study investigated the role of graphene oxide as a chelator to dissolve the amyloid-β plaques in AD using the density functional theory study.They have determined the chelating ability of various metals and GO by comparing the binding energies between metal-chelator and metal-Aβ complexes and conclude that GO can be used in future AD drug delivery therapy to target toxic metal-Aβ interactions and reduce Aβ aggregation [117].
GO may block the mTOR signaling pathway and initiate autophagy in microglia and neurons.When microglia and neurons were co-cultured, GO triggered autophagy in both cell types, particularly in the microglia, which aided in the removal of Aβ and ultimately had a protective impact on the neurons.Additionally, GO was able to decrease the toxicity of Aβ to neurons by its clearance in addition to being non-cytotoxic to microglia and neurons.These findings demonstrate the possibility of GO as an AD treatment [118].
Carbon nanotubes (CNTs) have garnered attention for their unique properties and biomedical potential.The ability of high drug loading, along with the capability to readily cross the BBB and also facilitate the passage of drugs to the brain via the olfactory route with ease, opens up new possibilities for targeted drug delivery and neuroprotection.In recent research, β-cyclodextrin modified CNTs nanocomposite was prepared for delivery of donepezil hydrochloride drug for the treatment of AD and found the significant sensitivity and limit of detection [119].
Since their unique characteristics, such as their ability to easily pass through cell membranes, thermal properties, large surface areas, and ease of molecular modification, carbon NPs stand out as highly innovative materials that could be used in novel therapeutic regimens against CNS.However, their usage in humans is also constrained, mostly due to the beginning of toxic phenomena that impact the nerve cells and the onset of inflammatory and oxidative processes.The focus of the new research must now be on the hunt for novel, more useful target molecules while also using appropriate engineering to structure nanomaterials that are better suited for human use [120].

Lipid-Based Nanocarriers
The abovementioned constraints are addressed using nanotechnology-based methods that utilize liposomes, micelles, dendrimers, and solid lipid nanoparticles (SLNPs) as DDSs.This study focused on medication delivery to treat NDs using an SLNP formulation [121].Notably, SLNP can pass physiological barriers to increase bioavailability without using high-dosage forms, direct the active compound toward the target site with a significant reduction in toxicity to the adjacent tissues, and protect drugs from chemical and enzymatic degradation.We believe that SLNP may be an effective method for medications to cross the BBB and reach damaged parts of the CNS in patients with NDs such as AD and PD [122].One study showed that nicotinamide-loaded functionalized SLNPs improved cognition in AD animal models by reducing the tau hyperphosphorylation [123].Rivastigmine tartrate-loaded SLNPs have been formulated for enhanced intranasal delivery to the brain in the Alzheimer's therapeutics [124].In a therapeutic study on AD treatment, RVG29functionalized SLNPs were prepared for the delivery of quercetin to the brain, resulting in a 1.5-fold increase in drug permeability to the experimental cell line [125].
Small vehicles (≤100 nm) are frequently preferred because only specific sizes can pass through the BBB in AD.However, studies have demonstrated that liposomes between 100 and 140 nm offer several benefits, including a longer half-life in blood circulation and a lack of plasma proteins [126].In a recent study, transferrin-functionalized liposomes conjugated with vitamin B12 were used as therapeutic agents for AD.The formulation targeted the BBB and neuronal cells and delayed the formation of Aβ fibrils, showing great potential for AD therapeutics [127].Caffeic acid-loaded transferrin-functionalized liposome NPs were developed capable of preventing AD by blocking Aβ aggregation and fibril formation and disaggregating mature fibrils [128].
Numerous studies have demonstrated the effectiveness of dendrimers as DDSs for the treatment of various diseases [129,130].Since positively charged NPs, in conjunction with mucus, have greater cellular absorption, as described in a previous study [131], superficially positively charged dendrimers are thought to facilitate enhanced drug transport to the brain.A recent study revealed that polyamidoamine (PAMAM) dendrimers are suitable for the delivery of donepezil, an AChE inhibitor used to treat AD, have good in vivo pharmacokinetics and can cross the BBB [132].Tacrine and PAMAM dendrimers codelivered as therapeutic molecules for AD treatment were observed to help reduce the side effects of the drug in an animal model [133].In the ND therapeutic study, carbamazepine was co-administered with PAMAM dendrimers in zebrafish larvae, resulting in reduced side effects from the carbamazepine [134].
Nanoliposomes are a feasible and promising DDS for AD that has not yet been tested in clinical trials.They are highly biocompatible and can carry various therapeutic molecules across the BBB and brain cells.They can be tailored to extend blood circulation time and directed against individual or multiple pathological targets.
In comparison to equivalent free drug solutions/suspensions, nano-lipid drug delivery systems have been shown to have positive properties such as prolonged drug release, increased CNS bioavailability, and further improved therapeutic efficacy [135].

Polymeric Nanoparticles
Polymeric NPs are solid objects composed of organic colloidal NPs with polymetric, natural, or artificial materials.Numerous monomers can be used to create polymeric NPs, which can then be polymerized using various methods, and their characteristics can be tailored for diverse applications.Synthetic, natural, and hybrid polymeric nanoparticle systems are most frequently used for brain targeting [136].Chitosan and PLGA are the most common polymeric NPs used in AD treatment.Mathew et al. conducted an in vitro study of PLGA-coated curcumin with Tet-1 in AD treatment, finding that PLGA-coated curcumin NPs have the potential for AD treatment because of their anti-amyloid and antioxidant properties [137].Another study showed that PLGA NPs loaded with Aβ generation inhibitor S1 and curcumin remarkably decreased the level of Aβ, enhanced the activities of antioxidant enzymes, and attenuated memory deficits and neuropathology in AD mice [138].A recent study found that a formulation of PEGylated biodegradable poly (lacticco-glycolic) nanospheres loaded with dexibuprofen administered to APPswe/PS1dE9 mice reduced memory impairment and decreased brain inflammation more efficiently than the free drug [139].
The size, shape, and chemical and physical properties of the NPs included in this review were not uniform.Each nanoparticle has unique properties with many advantages and disadvantages.The advantages and limitations of these NPs as potential DDSs have been discussed in many articles; however, scientists and researchers are working on most nanomaterials to study their uniformity, drug loading, drug release capacity, and safety as DDS for treating AD and other neurological diseases.Several in vitro and in vivo studies have demonstrated the significance of different types of NPs for treating AD.A few of these are discussed in Table 2, along with their results and possible prospects or limitations/advantages.Clinical failures might be brought on by polymeric nanoparticles' potential toxicity and sluggish degradability.The capacity of the polymeric NPs to traverse the BBB is constrained without surface changes.Although these NPs have a good rate of disintegration, the chronic nature of neurodegenerative illnesses and the requirement for repeated doses of the therapeutic substance could result in polymer accumulation that could have unwanted side effects [78,175].

Discussion
Mental and CNS illnesses have a significant prevalence worldwide, including neuroinflammation, brain tumors, and NDs.Neuronal loss is the main characteristic of NDs.AD and PD are the most common NDs.Although several medications are now approved for managing NDs, most treat only the related symptoms [176].Because of the presence of the BBB, developing therapeutic agents for various CNS-related disorders is highly challenging [177].
The BBB serves as the primary barrier to drug delivery in AD treatment.The physical and biochemical barriers of the BBB limit the effects of all hydrophilic drugs; efflux pumps inside the BBB frequently transfer lipophilic drugs back into the blood [178].As a result, it is critical to understand the structure and activity of the BBB to suggest alternative methods for delivering AD medications via nano-DDS.Utilizing the endothelial cell-binding affinity of lipid-soluble NPs can increase the rate at which a drug is transported via endocytosis or lipophilic transcellular routes.Moreover, the adsorptive properties of NPs can be useful because they can adhere to blood capillaries in the BBB, boosting the likelihood that the target medicine will cross this barrier [179,180].Altering NPs with specific receptors, carrier proteins, and receptor-mediated transcytosis can enhance medication uptake through the BBB.Despite the ability of NPs to pierce the BBB, only approximately 5% of medications reach the brain, leaving the remaining 95% at an ineffective location [181].This phenomenon may cause systemic side effects because the conventional route of drug administration is ineffective for accurately delivering the agent to the brain.The transport of therapeutic substances to the CNS via the olfactory and trigeminal nerves of the nasal cavity is facilitated by intranasal administration.
Furthermore, intranasal administration is risk-free and non-invasive.This medicine can prevent hepatic first-pass metabolism and drug degradation, increasing drug bioavailability [182].Nanotechnology is a cutting-edge method that may open the door to new ways to overcome blood-CNS barriers, particularly the BBB.The therapeutic effects of drug delivery systems depend on their capacity to bypass the immune system, pass through the BBB, and locate themselves in the target tissues [1].NPs are widely used in the diagnosis and treatment of AD [183]; however, for successful results, several aspects must be considered, including the target-specific distribution and metabolism of NPs and the interactions between target molecules (Aβ/Tau/NFT) and NPs.Nanomaterials have good in vitro inhibitory efficiency; however, the in vivo inhibition efficiency needs to be increased [184].Several metallic NPs provide a good platform for efficient inhibition of the aggregation of Aβ either directly or after conjugation with a drug molecule [185].
Traditional DDSs are ineffective because they cannot pass through the BBB.Although innovation in research ensures the creation of nanotheranostics, a major issue is its potential for use in human therapies.The BBB can be crossed by a number of NPs [186].Researchers are working on the development of nanomedicine using different types of nanocarriers.Table 2 summarizes some of the in/ex vivo studies.Nanoliposome carriers are the most promising drug delivery methods because of their biocompatibility and high flexibility in delivering a variety of therapeutic compounds across the BBB and specifically targeting brain cells.Evidence demonstrates that PSLs can cross the BBB to enter the brain, where they interact with several types of neuronal cell receptors [93].
It is possible to achieve widespread drug delivery to the entire brain by opening the BCFB instead of the BBB because the BCFB is relatively leaky compared to the BBB; watersoluble substances that do not cross the BBB do so on the BCSF barrier and enter CSF at a rate inversely related to molecular weight [187].Kung Y et al. (2022) effectively validated a strategy for noninvasively and selectively opening the BCFB to promote medication administration into CSF circulation by facilitating drug delivery in the CNS by opening the BCFB barrier with a single low-energy shockwave pulse [188].
A promising prospect for the L-type amino acid transporter 1 (LAT1)-mediated brain delivery of CNS medicines is provided by the relatively high expression of the LAT1, which is primarily expressed in the cerebral cortex, blood-brain barrier, and blood-retina barrier.The transporter has proven to be effective in delivering clinically used CNS medications and prodrugs like L-Dopa.The bulk of the time, a parent medication has been conjugated to an amino acid side chain using a biodegradable linker without substituting carboxyl and amino groups in order to effectively bind LAT1 [189].
An advanced method for combating MDR in cancer treatment is small interfering RNA (siRNAs) delivered by nanocarriers.This method increases the effectiveness of already available medications by inhibiting the no-flux and efflux-related protein pumps that are engaged in or overexpressed in the MDR [190,191].This type of nanocarrier-based siRNA technology may be helpful for treating CNS conditions.Moreover, the downregulation of the pump involved in drug resistance, combining monotherapy with P-gp inhibitors, and bypassing of pumps related to drug efflux are common nanotechnology methods that could be used to overcome the MDR problem in AD treatment.
The rapid development of nanotechnology has made many promising nanomaterials available for biomedical applications.These materials are widely used in the treatment of ND and appear to compensate for some of the shortcomings of stem cell therapy, including the transportation of stem cells, genes, and drugs, control of stem cell differentiation, and real-time monitoring.Therefore, stem cell therapy combined with nanotherapeutic techniques is a promising therapeutic method for treating NDs [192].Because nanomedicine has been a research area for approximately 20 years, discussing what the field should do in the next 20 years is appropriate for creating a framework based on science for ongoing, sustained progress [193].
Nanomedication particles have good stability, are less toxic, and cause fewer side effects when used to diagnose and treat AD in elderly patients.These particles also help patients live more comfortably and have favorable clinical outcomes [142].
Therefore, future research on NP-based brain delivery should concentrate on enhancing safety, precision targetability, and pharmacokinetic characteristics.Human clinical trials should be conducted to assess the efficacy and safety of certain NPs and to determine the most promising and affordable AD treatments.To ensure the safe use of NPs by patients and healthcare personnel, thorough handling and administration standards must be devised.In addition, for the future treatment of AD, the theranostic development of NPs is essential, promising substantial advancements in precision and customized therapy.The clinical outcomes of each patient with AD who received one of these tailored medicines greatly improved.They strongly emphasize evaluating the efficacy and safety of the treatment processes.Thus, NP-DDSs offer strong therapeutic promise for AD.Further translational research should be conducted to examine the interaction of NPs in a biological interface in light of the benefits of crossing the BBB and therapeutic modalities, including symptomatic alleviation, DMT therapy, and hallmark diagnostics.Future alternatives for treating and diagnosing AD are promising when NPs are combined with recently discovered medicines [194].
However, the number of patents for nanotechnology-based goods is increasing.Clinical trials are required to assess the therapeutic efficacy and potential toxicological effects on human health.Neurologists and patients will soon benefit from appropriate nanotechnology-based DDSs that may improve therapeutic outcomes at lower costs.Although no clinical studies have been conducted on using nanotechnology to treat AD, this field of medicine is projected to change, bringing new ways to diagnose AD and the ability to individualize a patient's therapy profile [195].

Current Research and Future Directions of Nanomedicine
AD is one of the most devastating diseases of the CNS.The primary pharmaceutical obstacle to the effective treatment of AD is BBB and BCFB.BBB-targeted nanomedicine has recently been developed and is now given more consideration in treating AD.Numerous nanoformulations, as indicated in Table 2, have proven to be highly effective in laboratory and clinical investigations.However, clinical translation from bench to bedside is not particularly successful because of an inadequate understanding of the mechanisms of action, the fate of nanocarriers inside the body, systemic toxicity, biocompatibility, aggregation, and the quick clearance resulting from their nanometer size.Comprehensive and indepth toxicological research should be focused on brain-targeting nanoformulations.The therapeutic potential of nanomedicine will depend heavily on the rational approach and ongoing design of nanomaterials based on in-depth and extensive knowledge of data gathered from biological processes.Polymeric NPs have shown potential toxicity, drug loading into lipid NPs for hydrophilic compounds is weak, and the in vivo stability of liposomes is subpar.Nano-emulsions exhibit poor stability during storage, which causes phase separation and a quick release effect.Dendrimers have toxicity problems as well.To optimize all of these concerns and handle them in the near future, additional in-depth research investigations are, therefore, necessary.
The major challenges for the development of nanomedicine for AD are shown in Figure 5; however, some critical limitations/challenges are as follows: 1.
Different kinds of functional groups; 3.
Different research study has different protocols and show different biodistribution of nanomedicine at different times; 4.
The ability of nanomedicine to control its morphological as well as chemical properties in the bloodstream/stability in blood; 5.
Nanomaterial does not show aggregation and is non-toxic, target-specific along with being pharmacodynamic and pharmacokinetic; 6.
Should cross BBB and another barrier of CNS.

Conclusions
The tremendous efforts currently needed to treat AD revolve around delivering the correct pharmaceuticals into the right neurons and obtaining enough of the right treatments for the brain parenchyma.However, many unanswered questions and gaps remain There are a few important things to consider regarding the nanomaterials utilized in the formation of nanomedicine: they are environmentally friendly; cross the BBB; nontoxic by nature; effective; and safe.In addition, nanomedicine delivery must be simple and non-intrusive.

Conclusions
The tremendous efforts currently needed to treat AD revolve around delivering the correct pharmaceuticals into the right neurons and obtaining enough of the right treatments for the brain parenchyma.However, many unanswered questions and gaps remain regarding the use of NPs for the treatment of neurodisorders, even though many studies have concentrated on the application of NPs in DDDs to overcome the obstacles faced by traditional medicine.Nanocomposites, including metal/inorganic NPs, CDs, QDs, and lipid NPs, have been used to treat AD and other CNS disorders.However, the nanomaterial itself may be cytotoxic and facilitate the passage of neurotoxic compounds across the BBB.Some administration methods may be more invasive or even cause a breach of the BBB, favoring the entry of infections or toxic substances into the brain.Therefore, studying the limitations of these NPs is necessary.
The most recent developments in this promising subject discussed in this review article can offer systematic knowledge for designing new initiatives and improving the use of NPs to treat AD.

Figure 3 .
Figure 3.A graphical illustration of possible pathways of nanomaterial-based DDSs that effectively cross the blood-brain barrier for treating Alzheimer's disease (created with BioRender.comaccessed on 10 August 2023).

Figure 3 .
Figure 3.A graphical illustration of possible pathways of nanomaterial-based DDSs that effectively cross the blood-brain barrier for treating Alzheimer's disease (created with BioRender.comaccessed on 10 August 2023).

Figure 4 .
Figure 4.A general overview of nanoparticles used as drug delivery carriers in the management and treatment of AD (created with BioRender.comaccessed on 10 August 2023).

Figure 4 .
Figure 4.A general overview of nanoparticles used as drug delivery carriers in the management and treatment of AD (created with BioRender.comaccessed on 10 August 2023).

Table 1 .
Therapeutic targets for management and treatment of AD (Individual image was adopted from BioRender.com; 10 August 2023).
[26,27]teinThe misfolded Tau is self-assembled, forming a Tau oligomer, and then, Tau inclusions lead to AD Reduction in toxic Tau gain of function may be an effective therapeutic strategy for AD Gosuranemab, lonafarnib tilavonemab, semorinemab, zagotenemab,[26,27]Neurofibrillary tangles Excessive Tau phosphorylation and aggregation are the key processes in the formation of NFT that cause neuron death and lead to AD Prevent phosphatase activity; promote microtubule stability; reduce Tau aggregate and formation of NFT

Table 1 .
Therapeutic targets for management and treatment of AD (Individual image was adopted from BioRender.com; 10 August 2023).

Table 1 .
Therapeutic targets for management and treatment of AD (Individual image was adopted from BioRender.com; 10 August 2023).

Table 1 .
Therapeutic targets for management and treatment of AD (Individual image was adopted from BioRender.com; 10 August 2023).

Table 2 .
Summary of Nanocarriers Used for AD treatment (only in/ex vivo study mentioned here).