SLNs are thought to be desirable colloidal drug delivery methods for brain targeting. The ability of these formulations to cross the BBB, which enables the medicine to enter into the CNS in useful quantities, is one of the most intriguing problems they face. High drug concentrations are required for neuroprotection, a situation that is challenging to attain due to efflux processes that move treatments from the brain to circulation and, most importantly, because medications are unable to penetrate the BBB. SLNs have emerged as a promising candidate in terms of safety, stability, low toxicity, large scale production, and drug loading. Many researchers attempted to address this problem in recent years using medicinal chemistry-based strategies and modern drug delivery systems (Sozio et al., 2010; Cacciatore et al., 2012).

It was discovered in one study involving the encapsulation of piperine, a natural alkaloid with a polyene bond system which provides antioxidant property and a tertiary nitrogen for mimicking the acetylcholine structure. Its administration to the brain is difficult to achieve as it undergoes extensive metabolism in the liver, carries risk of polymerization, and poor water solubility. To address this, SLNs were made with glycerol monostearte and various coatings, like polysorbate-80, for effective brain targeting. In vitro and in vivo testing revealed that SLNs of piperine coated with polysorbate-80 reduced superoxide dismutase levels, reduced cholinergic degradation, caused minimum immobilization in the animal, and reduced the presence of amyloid plaques (Yusuf et al., 2013).

A natural flavonoid quercetin was formulated into the SLN as a potential medicinal moiety for the treatment of AD. It was discovered that treating aluminum chloride-treated rats with quercetin-loaded SLN revealed decreased neurodegenerative effects and, more specifically, that the antioxidant capacity of quercetin was greatly enhanced by SLN formulation (Dhawan et al., 2011).

The liquid lipid causes disarray in the lipid matrix of the NLC, allowing for increased encapsulation efficiency and minimal ejection of the encapsulated medication during storage. As a result, the current research focuses on the NLC as a nanocarrier for brain targeting. NLC has benefits over other nanosystems for nasal medication delivery since it is made from biocompatible and biodegradable materials such as physiological lipids and other excipients. Furthermore, the NLC shields medicines from enzymatic breakdown, extends nasal cavity residence duration, and enhances bioavailability. Furthermore, the NLC with desirable properties for nose-to-brain delivery can be produced (Jojo et al., 2019; Cunha et al., 2021).

Optimized pioglitazone-loaded NLCs are used for nose-to-brain administration in one of the reported studies. Pioglitazone is an antidiabetic medication that might be used to address numerous targets in AD. The formulation was found to be safe for nasal administration in an in vitro nasal ciliotoxicity investigation. After nasal injection, in vivo biodistribution showed that pioglitazone-loaded NLC delivered more pioglitazone to the brain, suggesting the potential of NLC as an effective pioglitazone carrier in AD therapy (Chintamaneni et al., 2017).

LDCs as a drug delivery device aid in improving the medication’s lipophilic properties. Due to its particle size and surface characteristics, LDCs are vital for brain-targeted drug delivery (Figure 2). As a result, LDCs are formed as nano-LDCs using high-speed and high-pressure homogenization procedures to produce particles in a particle size range of 100–200 nm that can pass through the GI tract and the BBB. Positive allosteric modulators (PAMs) of M1 muscarinic receptors have no agonist action, but when attached, they increase the affinity of the orthosteric ligand, ACh. The bioavailability of these PAMs in the brain is one of their primary drawbacks. The bioavailability of PAMs of the M1 receptor has been found to be improved by surface-modified nano-LDCs (Chintamaneni et al., 2017). When used in conjunction with AChE inhibitors, they are predicted to improve the effectiveness while lowering therapeutic dose and adverse effects. PAMs can be made as LDC nanoparticles coated with polysorbate-80 to improve oral bioavailability and its penetration to the CNS while simultaneously lowering clearance.

MEs are pseudoternary compounds that are thermodynamically stable, are isotropic in nature, and have low-viscosity physicochemical features. ME droplet sizes range from 10 to 140 nm. Due to less particle size, they are both optically clear and thermodynamically stable (Figure 2). MEs have a number of benefits, including the ability to carry high amounts of lipophilic and hydrophilic medicines, as well as focused and regulated drug administration, and are thus being studied extensively for intranasal delivery in brain targeting. ME components such as oils, surfactants, and cosurfactants generally serve as absorption enhancers, P-glycoprotein (P-gp) inhibitors, and improve drug uptake in the brain in order to cross the BBB. To increase brain delivery, functional MEs might be created using such functional additions (Kamaly et al., 2016). Ibuprofen was repurposed using the ME strategy in the therapy of AD and was found effective in brain targeting via the intranasal route as compared to oral and intravenous routes (Wen et al., 2021). Oils such as oleic acid along with Tween 20, ethanol, and propylene glycol as surfactants and cosurfactants in ibuprofen-repurposed o/w ME helped as penetration enhancers on the tight junctions and enzyme inhibitors in the nasal cavity to overcome enzymatic degradation in the nasal cavity.

Thermodynamic stability and enhanced pharmaceutical design make these nanosized emulsions (NEs) attractive platforms for successful transport of bioactive molecules across the BBB. NE as a viable medication delivery strategy for the therapy of neuronic illnesses is enabled by innovative surfactants and cosurfactants. Their tiny particle size (50–500 nm) allows for homogeneous dispersion of medicines and a larger payload for site-specific delivery (Figure 2). Intranasal medication delivery with a memantine-embedded NE has been described. This method circumvented the BBB and successfully delivered memantine in the treatment of AD. In simulated nasal fluid, the NE had a mean globular size of approximately 11 nm and 80% drug release. Intranasal injection of a memantine-loaded NE resulted in increased antioxidant effectiveness and improved cellular absorption in experimental rats’ brain cells. The oil by water (o/w) donepezil hydrochloride-loaded NE was made with 10% labrasol and glycerol. The AD-infected brain cells were influenced by nanoscale, homogeneous, and stable particles of NE. The nasal route was used to study the cytotoxicity in Sprague–Dawley rats, which indicated dose-dependent effectiveness without disrupting the cell shape. The antioxidant and radical scavenging effectiveness of donepezil hydrochloride NE demonstrated great potential for treating neurological disorders. The scintigram results determined the maximal cellular absorption of donepezil hydrochloride by brain cells (Cunha et al., 2021).

Liposomes are self-aggregated, lipidic nanomolecules that combine and deliver lipophilic, hydrophilic, nucleic acid components and proteins to the CNS. Liposomes with lipophilic properties aid medication transportation through the endothelium cells inside the brain and allow excellent absorption in the brain (Vieira and Gamarra, 2016; Hong et al., 2019; Pathak et al., 2021). The two most common routes for drug release from liposomes are drug diffusion and liposomal endocytosis. The structure and lipid composition of vesicles, on the other hand, have an effect on their transportation via circulation and cellular absorption in the brain cells. The vesicular morphology of liposomes helps in delivery of both hydrophilic and hydrophobic neuroactives. The liposome research has shown that they have a wide range of pharmacological activities like anti-ischemic, neuroprotective, antiepileptic, and antibacterial properties. These formulations have been investigated as cargos for therapeutic import across the BBB by active targeting (Pathak et al., 2021). One of the research projects includes the development of curcumin-loaded liposomes for the effective treatment of AD. Curcumin-loaded liposomes illustrated antiamyloid properties. The findings showed that amyloid poisons generated in the brain endothelium area possess neuroprotective properties. Curcumin’s phenolic group binds to amyloid proteins, reducing the deposition of plaque and facilitating an aggregation-free environment surrounding the brain cells (Behl et al., 1994).

Niosomes are made up of nonionic surfactants that self-assemble in an aqueous system, making them more versatile and durable than liposomes while also lowering the drug permeability. One of the experiments undertaken by researchers focused on the possibility of unique dual drug-loaded niosomes for the nasopharyngeal transport of rivastigmine and N-acetyl cysteine to the CNS. The dual drug-loaded niosomes had a size distribution of 162 nm with an encapsulation efficiency of 97% for rivastigmine and 85% for N-acetyl cysteine. The dual drug-loaded niosomes’ drug release pattern sustained up to 2 days. Free drug formulations had a greater combinatorial impact than inhibition experiments for the enzymes acetyl cholinesterase and DPPH (1, 1-diphenyl-2-picrylhydrazyl). After a 2-day nasal permeation, the niosomes’ efficacy and biocompatibility were established. In vivo pharmacokinetic and organ biodistribution experiments have revealed that the niosomes had a superior pharmacological profile and a wider distribution in the brain than other organs, indicating targeted nose-to-brain delivery (Saraswathi et al., 2021).

Phytosomes are made up of individual components from herbal extracts linked to phosphatidylcholine (Figure 2). In India, Geophila repens is a climbing plant found to have anticholinesterase qualities and hence is used for improving memory performance. The antioxidant capabilities of Geophila repens leaves were examined and found to be significant, presumably attributed to the prevalence of triterpenoids, phenolic chemicals, and flavonoids. Systemic absorption of phytochemical compounds via the BBB is challenging for developing phytoformulations for AD therapy. To overcome these concerns, the Geophila repens phytosome-loaded intranasal gel was prepared with better nasal–brain penetration capabilities. In this experiment, transcutol was used as a permeation enhancer, while hydroxypropyl methyl cellulose (HPMC) was used as a gelling agent. During ex vivo studies, this gel exhibited significant penetration across the nasal mucosa without any irritation. Furthermore, it had a similar proportion of acetyl cholinesterase inhibition to donepezil (97%) but was higher than 20% from normal Geophila repens leaves’ gel and accelerated angiogenesis, indicating that it has the potential to change the cognitive behavior of Alzheimer’s condition in patients (Rajamma et al., 2022).

Exosomes are nano-sized extracellular vesicles produced by endosomes and released by practically all cell types. Exosomes are abundant in biological fluids and CNS tissues (Figure 2). Their contents change during illnesses, making them an appealing target for innovative diagnostic techniques. Exosomes have been demonstrated to transfer toxic amyloid-beta and hyperphosphorylated tau across cells, thus triggering apoptosis and contributing to neuronal death. On the other hand, exosomes appear to have the capacity to lower amyloid-beta levels in the brain via microglial absorption and transport neuroprotective chemicals across cells. Exosomes are particularly fascinating from the point of creating innovative treatment methods because of these characteristics, among many others. Exosomes generated from the CNS are also prevalent in physiological fluids, making them a promising target for biomarker development (Zhang et al., 2019). Exosomes have been implicated in AD since their discovery, and various investigations have established their multiple functions in the disease. Exosomes appear to be valuable in a variety of ways in the diagnosis and treatment of AD, such as reducing the extracellular amyloid load or functioning as early indicators of the illness (Cai et al., 2018; Soliman and Ghonaim, 2021).

Magnetosomes have attracted a lot of attention in recent years, and they are being employed for both diagnostic and therapeutic applications (Gorobets et al., 2017). With their neutral nature and low cytotoxicity, magnetosomes may be effective in brain disorders like AD (Figure 2). One of the investigations reveals that magnetic nanoparticles can permeate the normal BBB when a mouse model is exposed to an external magnetic field. An electromagnetic controller was developed to strategically direct magnetite-containing drugs. These nanoparticles were able to cross the BBB after being exposed to external electromagnetic fields of around 28 mT (0.43 T/m). Magnetic nanoparticle absorption and transportation rates in the brain were also dramatically boosted by a pulsed magnetic field. The localization measured by fluorescent magnetic nanoparticles demonstrated the viability of magnetic nanocontainers as a useful targeted device for AD diagnosis and treatment (Kong et al., 2012).

Dendrimers are the most symmetric, hyperbranched, and homogeneous nanosized carriers that can deliver water-soluble or -insoluble, high- or low-molecular weight molecules either by passive or active mechanisms by intravenous, intraperitoneal, or intranasal routes of administration. In situ mucoadhesive gels showed enhanced radioactivity in the brain post intranasal delivery of aqueous, radio-labeled siRNA-dendrimer complex (dendriplexes), owing to the diffusion mechanism (Perez et al., 2012). Cationic charged surface of dendriplexes improves the association with mucus and, hence, promoted drug delivery to the brain. Polyamidoamine (PAMAM) dendrimers with 15-nm size helped in brain targeting of a poor water insoluble and antipsychotic drug haloperidol by intranasal and intraperitoneal routes of administration (Katare et al., 2015). Intranasal delivery of haloperidol showed better targeting to the brain, especially in the striatum than intraperitoneal delivery and that too at 6–7 times lower dose. Additionally, it could be derived from this study that the intranasal delivery can help in decreasing the CNS side effects by lowering the plasma drug concentration and is used in the management of AD (Aliev et al., 2019) (Figure 2).

Carbon nanotubes (CNTs) are inorganic materials made of graphite sheet tubes of nanosized dimensions. CNTs can be either single-walled or multi-walled, with open ends or may be closed with fullerene caps. Recently, multi-walled carbon nanotubes (MWCNTs) have been found to exert neuroprotective effects by the modulation of vital neurotrophic factors when delivered via the intranasal route (Soligo et al., 2021). Electroconductive MWCNTs have the potential for targeted delivery to various areas in the brain, especially the limbic region, which is the focal point for progression of major neurodegenerative diseases (Figure 2). Thus, MWCNTs can be useful in the therapy of early diabetic encephalopathy, characterized by acute neurodegeneration and poor neurocognitivity (Lohan et al., 2017). CNTs are associated with several serious toxicities such as cellular, respiratory, liver, dermal, subcutaneous, central nervous system, kidney, cardiovascular, and eye toxicities (Mohanta et al., 2019). In case of CNS toxicity, the interaction of CNT with brain cells leads to the release of different mediators/chemicals from microglia and astrocytes that may result in apoptosis, inflammation, and oxidative stress in the brain (Bardi et al., 2013).

Nanomicelles are nanosized carriers (particle diameter 10–100 nm) molded by self-association of amphiphilic surfactants or copolymers in aqueous solutions (Bose et al., 2021). It comprises a core (hydrophobic) and a shell (hydrophilic) (Milovanovic et al., 2017). Mixed nanomicelles are more stable and ensure better aqueous solubility and drug-loading efficiency. Stable nanosized mixed lurasidone micelles showed sustained release and better brain targeting of lurasidone hydrochloride by the intranasal route than the intravenous route. The nanosize of lurasidone micelles allowed improved delivery to brain tissue via olfactory and trigeminal systems, bypassing the BBB (Pokharkar et al., 2020). PEGylated nanomicelles helped in better uptake by olfactory and trigeminal pathways of cell-penetrating peptides (CPPs) owing to enhanced diffusion across the brain stroma (Kanazawa et al., 2017). Thus, nanomicelles are useful in brain targeting of CPPs, which possess the challenge of limited dose to overcome potential immunogenicity problems.