Transport of chemicals across an epithelium through the intercellular gaps between epithelial cells is known as paracellular transport, which is a passive transport mechanism. Tight junctions are essential for the paracellular movement of macromolecules across the epithelium, according to a substantial body of research. For particles to penetrate through the paracellular route, it is the main rate-limiting channel. The tight junctions consist of a complex mixture of intracellular plaque proteins, several regulatory proteins that attach the transmembrane proteins to the actin cytoskeleton, and transmembrane integral proteins such as claudins, occludin, and junctional adhesion molecules (Shamloo et al., 2016[87]).

Uses a variety of mechanisms, including passive diffusion, transcytosis, and receptor-mediated transport. The physical and chemical properties that affect BBB permeability include molecular weight (only the molecules under 400-600 Da), charge (Positive Charge), lipid solubility, surface activity, and relative molecule size. While the entry of hydrophilic molecules is typically suppressed, the enormous surface area of the endothelium membrane provides an efficient transcellular passive diffusion channel for lipid-soluble drugs and tiny gaseous molecules (Kadry et al., 2020[47]; Shamloo et al., 2016[87]).

As mentioned above, these properties of the BBB prevent the pharmacological therapy of some neurological disorders from reaching the brain. It should be noted that the existence of the P-glycoprotein pump in the BBB, which enables the recognition of molecules necessary for the brain to enter the brain and the expulsion of other molecules, which includes medicines, represents a further barrier for drugs crossing the cerebral capillary endothelium and entering the brain parenchyma. For these reasons, various strategies have been investigated in order to improve the permeation of drugs across the BBB (Jiang et al., 2016[45]; Miao et al., 2019[65]).

a) Blood-brain barrier transient disruption

This method makes use of unpleasant substances or hyperosmotic solutions to decrease the brain's endothelial cells by dissolving tight junctions, allowing various chemicals to enter the cerebral tissue. However, it is important to keep in mind that this particular approach does include some disadvantages, it may damage the BBB's integrity and physiological activities, potentially causing the build-up of neurotoxic, xenobiotic, and exogenous substances, which could harm the CNS (Bang et al., 2017[7]; Gao et al., 2017[29]).

b) Intracerebroventricular and intrathecal infusion

The techniques used in this method include the administration of therapeutic proteins by intraventricular infusion, which involves the direct injection or infusion of these proteins into the cerebrospinal fluid (Dong, 2018[21]).

The majority of non-invasive approaches include pharmacological tactics that can change the way medications are transported over the BBB like increasing lipid solubility, using transport or carrier systems, inhibition of efflux transporters, trojan horse approach, chimeric peptide, monoclonal antibody fusion proteins, gene therapy, intranasal drug delivery and nanoparticle technologies (Sharma et al., 2021[88]; Tam et al., 2016[96]). This strategy focuses mostly on using nanotechnology to release drugs into the brain. The current efforts are mostly concentrated on improving NPs' capacity to accurately target the therapeutic site, hence reducing the doses of medicines released at unwanted places (Sharma et al., 2021[88]; Yamamoto, 2018[110]).

There are numerous types of nanoparticle (NP)-based medication delivery systems that have been developed. NPs can be broadly categorized into organic and inorganic nanoparticles (ONPs and INPs) based on their composition. ONPs are composed of carbon-based nanomaterials, while INPs do not contain carbon and are composed of inorganic elements e.g., silicon, gold and silver (Kim et al., 2020[51]; Nikalje, 2015[71]). However, there are some NPs composed of allotropes of carbon e.g., fullerenes, carbon nanotubes, graphene-based nano systems or graphene quantum dots (Figure 2(Fig. 2)).

Regarding size and shape control, convenience of preparation, and functionalization, INPs offer benefits over ONPs. Inorganic nanomaterials exhibit interesting mechanical, optical, physical and electrical phenomena at the nanoscale, which can be tailored through changes in material, phase, shape, size and surface characteristics. However, INPs also have disadvantages. INPs frequently require the addition of a biocompatible surface in order to prevent toxicity, especially for heavy metals (Barani et al., 2021[8]; Bastogne, 2017[9]; Kim et al., 2020[51]; Nikalje, 2015[71]). INPs may not degrade, which raises questions about their biocompatibility and biosafety. On the other hand, because carbon makes up a significant portion of our bodies, ONPs tend to have good biocompatibility. However, one of their drawbacks is that they are more difficult to prepare (Upadhyay, 2014[102]). Therefore, if we decided to categorize the various NP functions, we could say that ONPs are more interesting for drug delivery due to their higher biocompatibility and safety, while INPs are better for functionalization and monitoring purposes or for alternative treatments like photothermal therapy and hyperthermia. In order to integrate INPs and ONPs' benefits into a single carrier, hybrid Nps frequently blend the two (Khan et al., 2018[49]; Satapathy et al., 2021[86]) (Table 1(Tab. 1)).

Polymeric nanoparticles: Nanoparticles are solid colloidal particles with sizes typically between 60 and 200 nm. They have a polymeric core matrix in which pharmaceuticals can be embedded and are well suited for drug delivery due to their regulated drug release and targeting effectiveness. They are being extensively employed for the development of drug delivery carriers that can penetrate the blood-brain barrier (Abadeer and Murphy, 2016[1]; Nikalje, 2015[71]). Additionally, they can prevent the reticuloendothelial system from phagocytosing them, which will increase the concentration of medicines in the brain. For the treatment of AD, in vitro research demonstrated that the drug delivery to the brain could be increased by utilizing of polymeric nanoparticles, which causes a reduction in oxidative stress, inflammation, and plaque accumulation. Furthermore, an efficient target-specific delivery for application in brain cancer therapy was produced by the in vivo investigation involving the simultaneous delivery of the anti-cancer drug cisplatin and the antioxidant agent boldine utilizing polylactide-co-glycolic nanocarriers. Through the invention of a penetrating amphiphilic polymer-lipid nanoparticles' system, docetaxel can now be delivered for the treatment of brain metastases. The in vivo experiments showed that the nanoparticles accumulated at the tumor site and successfully suppressed tumor development, increasing median survival in comparison to an equivalent dose of clinically utilized docetaxel fluid formulation (Khan et al., 2018[49]; Nikalje, 2015[71]; Elzoghby et al., 2016[23]; Posadas et al., 2016[80]).

Liposomes: A lipid bilayer encircles a hydrophilic core in liposomes. Liposomes' amphiphilic properties allow for the encapsulation of a wide range of medicines with various polarity. Because lipids degrade rapidly in the digestive tract, it is the best to provide liposomes to the brain via (IV) or (IN) routes. Due to their ability to pass the blood-brain barrier and deliver the right amount of medications to the brain, liposome applications are typically used to treat brain tumors (Nikalje, 2015[71]; Raman et al., 2020[82]). NPs should never be larger than 200 nm because it is thought that some pores in human brain tissue are larger than 200 nm, although the majority are slightly larger than 100 nm. However, because liposomes are soft-matter NPs and hence highly flexible, they have advantages in this situation since they can pass through pores even if their sizes are greater than pore diameters (Mistretta et al., 2023[66]; Nikalje, 2015[71]). The disadvantage of such a soft composition is that liposomes are more fragile than, for example, other ONCs such as polymeric nanoparticles. According to numerous studying liposomal formulations have been used to deliver anti-cancer medications such as methotrexate, 5-fluorouracil, paclitaxel, doxorubicin, and erlotinib (Nikalje, 2015[71]).

Dendrimers: Dendrimers are globular, hyperbranched polymeric structures that resemble trees in structure. Dendrimers typically consist of a central core (a single atom or group of atoms), generations, repeat structural units connected to the core, and surface functional groups that may have positive, negative, or neutral charges. Dendrimers provide a number of benefits for drug delivery to the brain (Miao et al., 2019[65]; Shamloo et al., 2016[87]). First, their synthesis is precisely controlled, and a wide variety of ligands can be functionalized on their surface to promote BBB crossing. Then, because of their hyperbranched structure, these ligands are very well covered on the dendrimer surface, improving cellular recognition. Additionally, their small size and monodisperse composition enable better regulation of brain uptake. Moreover, the possibility of conjugating their cationic surface groups with nucleic acids makes dendrimers potential ONCs for gene therapy (Nikalje, 2015[71]; Thomsen et al., 2015[99]). Dendrimers have been used in the treatment of brain cancer, stroke, neuroinflammation, and neurodegenerative illnesses. AD has been treated with the anti-epileptic medication carbamazepine encapsulated (Nikalje, 2015[71]).

Micelles: Micelles are amphiphilic molecules with a particle size of 5 to 50 nm. Under certain concentration and temperature parameters for the aqueous solution, micelles spontaneously form. Micelles have gained attention for their use in the delivery of poorly water-soluble compounds, their capacity to provide sustained and regulated release, their ability to keep pharmaceuticals chemically and physically stable, and their improvement of therapeutic bioavailability (Baig et al., 2021[4]; Nikalje, 2015[71]).

Solid lipid nanoparticles: Particles with a solid lipid core that exist at body and room temperatures are known as solid lipid nanoparticles (SLNs). As a result of their lipophilic characteristics, SLNs can be employed as drug carriers by passing across the BBB and into the CNS via an endocytosis mechanism. By coating and conjugating SLNs, it is possible to reduce the cytotoxicity of SLNs and enhance the amount of medication delivered to the brain (Abadeer and Murphy, 2016[1]; Nikalje, 2015[71]).

Gold Nanoparticles: Gold Nanoparticles are inorganic particles having a gold core and surface ligands bound by covalent or non-covalent bonds. The shape (spheres, shells, or rods) and size of the particles can be altered depending on the synthesis process. Low concentrations of AuNPs of 10-15 nm were able to penetrate the BBB and reach the brain in a number of in vivo investigations on animals. However, the liver and blood contained the vast bulk of the injected amount. Additionally, the amount of gold discovered in the brain varied depending on the AuNP dose, with no evidence of saturation at the studied doses. This implies that the AuNPs might pass across the BBB via a non-saturable channel like passive transmembrane diffusion or the paracellular pathway (Bastogne, 2017[9]; Nikalje, 2015[71]; Posadas et al., 2016[80]).

Both the treatment of Parkinson's disease with L-DOPA functionalized multi-branched nanoflower-like gold nanoparticles and the treatment of AD with gold nanoparticles functionalized with -amyloid-specific peptides have been studied, and both have demonstrated improved blood-brain barrier permeability across in vitro models. It has also been investigated how the size of gold nanoparticles coated with insulin affects their ability to cross the blood-brain barrier. The findings demonstrated that the 20 nm-diameter nanoparticles had the widest biodistribution and accumulation in the brain (Nikalje, 2015[71]; Posadas et al., 2016[80]).

Carbon Nanotubes: A category of nanomaterials known as carbon nanotubes is composed of tubes made of graphite sheets with nanoscale diameters. Carbon nanotubes can have one or more walls, open ends, or fullerene caps to seal them. Drug delivery for the treatment of brain cancer has been used with polymer-coated carbon nanodots and chemically functionalized multi-walled carbon nanotubes. Both in vitro and in vivo studies revealed that the blood-brain barrier was penetrated and that tumors had increased absorption (Baig et al., 2021[4]; Nikalje, 2015[71]).

Quantum Dots: In terms of structure, QDs have a metalloid crystalline core, which will eventually determine the type of light it emits according on its composition and size. Cadmium and tellurium, which both form the core of QDs and have an average diameter of 2 to 10 nm (200-10,000 atoms), are one of the primary precursors utilized in the assembly of these quantum dots in nanotechnology (Bastogne, 2017[9]; Nikalje, 2015[71]). Among the known quantum dots are those made of carbon, selenium, silver, silicon and gold. Graphene quantum dots (GQDs) are currently receiving attention. One of the most recent additions to the group of carbon-based nanomaterials is GQDs. They are currently said to be helpful in treating Alzheimer's and Parkinson's disease. Additionally, it is now known that GQDs have antimicrobial and anti-diabetic properties. They are also currently being extensively tested for use in medicine delivery. They have good potential for medication delivery across the blood-brain barrier. GQD can also be used to deliver medication specifically to tumors (Abadeer and Murphy, 2016[1]; Nikalje, 2015[71]; Posadas et al., 2016[80]).

Synthesis of nanoparticles is a term used to describe production processes, top-down and bottom-up are the two most common techniques. Top-down method refers to the process of breaking down large materials into smaller ones. The bottom-up method depends on forming nanoparticles from atomic-sized components (Figures 3(Fig. 3) and 4(Fig. 4)). In general, nanoparticle synthesis can be carried out via physical, chemical, and biological methods, while the precise synthesis method depends on the material being created (Baig et al., 2021[4]; Jeyaraj et al., 2019[44]).

Mechanical milling: Mechanical milling is a physical process that transfers kinetic energy from the grind medium to the substance that is being reduced. Consolidation and compaction is an industrial-scale procedure that involves milling several components in an inert atmosphere, are used to create material with improved characteristics (do Carmo Lima Carvalho et al., 2023[20]).

Lithography: The method of lithography involves printing a necessary shape or structure on a light-sensitive substance whereas only removing a small amount of the material to produce the desired shape and structure (do Carmo Lima Carvalho et al., 2023[20]). The ability to manufacture anything from a single nanoparticle to a cluster with the desired shape and size is one of nanolithography's key advantages, but the main disadvantage is the need for advanced and expensive equipment (Khandel et al., 2018[50]).

Laser Ablation: Laser ablation synthesis produces nanoparticles by striking the target material with a strong laser beam. Due to the high energy of the laser irradiation used in the laser ablation process, the source material or precursor vaporizes, resulting in the creation of nanoparticles without the need for any chemical or stabilizing agents (Ealia and Saravanakumar, 2017[22]; do Carmo Lima Carvalho et al., 2023[20]).

Sputtering: Sputtering is a technique for creating nanomaterials by hitting solid surfaces with high-energy particles like plasma or gas, depending on the energy of the incident gaseous ions, physically eject tiny atom clusters. Sputtering typically involves depositing a thin coating of nanoparticles, followed by annealing (Ijaz et al., 2020[41]).

Thermal decomposition: Thermal decomposition is an endothermic chemical breakdown of a substance caused by heat, which destroys its chemical bonds. The temperature at which an element begins to chemically break down is known as the decomposition temperature. The metal is broken down at particular temperatures in a chemical reaction that yields secondary compounds, creating the nanoparticles (Thomsen et al., 2015[99]).

Sol-gel: The sol is a colloidal suspension of particles in a liquid phase. The gel is a solid macromolecule suspended in a liquid. Due to its simplicity, the majority of nanoparticles can be produced with this method, sol-gel is the most used bottom-up approach. It is a wet-chemical method that uses a chemical solution as a precursor for an integrated system of discrete particles. Precursors for the sol-gel method are frequently metal oxides and chlorides. The precursor is then mixed with the host liquid by sonication, shaking, or stirring, creating a system with a liquid and solid phase. Using a variety of techniques, including centrifugation, filtering, and sedimentation, a phase separation is performed to recover the nanoparticles, and the moisture is then further removed by drying (do Carmo Lima Carvalho et al., 2023[20]; Ijaz et al., 2020[41]).

Chemical Vapor Deposition (CVD): The process of depositing a thin layer of gaseous reactants onto a substrate is known as chemical vapor deposition. The deposition is carried out at room temperature by mixing gas molecules, in a reaction chamber. A heated substrate that comes into touch with the mixed gas experiences a chemical reaction (Bastogne, 2017[9]). A thin film of product is created during this reaction and is recovered to be used. The influencer of CVD is substrate temperature (Ealia and Saravanakumar, 2017[22]).

Pyrolysis: The most widely utilized method for producing nanoparticles on a big scale is pyrolysis. It involves using flame to burn a precursor. The precursor is either a liquid or a vapor that is fed under high pressure through a small hole into the furnace, where it burns. The nanoparticles are then air-classified from the combustion or by-product gases. To get a high temperature for simple evaporation, use plasma rather than a flame (Ijaz et al., 2020[41]; Khandel et al., 2018[50]).

Spinning: A spinning disc reactor creates nanoparticles by spinning them together (SDR). The physical parameters, such as temperature, can be adjusted by rotating a disc inside a chamber or reactor. To remove oxygen and prevent chemical reactions, the reactor is often filled with nitrogen or other inert gases (Khandel et al., 2018[50]). The liquid, such as water and precursor, is poured into the disc as it is rotating at various speeds. The atoms or molecules are fused together by the spinning, and the result is precipitated, collected, and dried.

Biosynthesis: Biosynthesis sometimes known as "green synthesis," is an eco-friendly method for creating non-toxic, biodegradable nanoparticles (Pinheiro et al., 2021[78]). Instead of using conventional chemicals for bio-reduction, biosynthesis uses bacteria, plant extracts, fungi, and yeast combined with the precursors to make nanoparticles (Jeyaraj et al., 2019[44]).

Physical method: Physical method uses mechanical pressure, high-energy radiation, thermal energy, or electrical energy to abrade, melt, vaporize, or condense the material to produce NPs. It doesn't need any chemical material but has a high waste product and less productivity with many difficulties in size and shape tenability that's why it's not a good method for preparing NPs with desired shape and size and has less stability. The physical methods of synthesis include (mechanical milling, sputtering, laser ablation, flame pyrolysis, spinning) (Navarro and Salas, 2022[70]).

Chemical method: Accomplished via chemical reduction using several organic and inorganic reducing agents, electrochemical methods, physicochemical reduction. The advantages of this method include high yield, controlled size, stability, easy preparation, and cost efficiency. Most common techniques in this field are the following: Chemical vapor deposition, the sol-gel method, lithography, thermal decomposition (Khandel et al., 2018[50]; Navarro and Salas, 2022[70]).

Biological method: The biological process involves creating nanoparticles utilizing plant extract (leaf, stem, root and fruit), bacteria, fungi, and microorganisms and there are many advantages of this method like: protecting the human health, low cost, economical, lesser waste product, and fewer accident. And it is the best method due to effectiveness, simplicity and non-toxicity (Kaur et al., 2023[48]).

The AMT gives nanoparticles a way to cross the BBB and enter the brain. This process is started by an electrostatic interaction between positively charged ligands and the negative-charged cell membrane. The glycocalyx of the BBB's endothelial cells, which is made up of the heparin sulphate proteoglycans (HSPGs) glypican and syndecan, covers their phospholipid-rich membrane (Dong, 2018[21]). On this side of the BBB, sialo glycoproteins and sialo glycolipids have a lot of carboxyl groups. All of them give rise to the luminal side of the BBB's significantly negative charge. As a result, AMT can be facilitated by the electrostatic interactions between the cationic groups of ligands conjugated on the surface of nanoparticles and the negative moieties exposed at the luminal surface of cerebral endothelial cells (Ding et al., 2020[19]).

The mechanism used to explain how NPs interact with the luminal surface of the BBB is based on how well their surfaces have been functionalized. By adding a positive charge to the NPs surface, this interaction can be facilitated given that endothelial cells have negative charges. This problem can be realized using a variety of techniques. The construction of NPs from materials that are positively charged at physiological pH is one option (Bellettato and Scarpa, 2018[10]).

The RMT is one of the most recently used drug delivery methods using functionalized NPs through the BBB endothelium. In endothelial cells, transcytosis begins with vesicular carriers bringing extracellular cargo within the cell. It is dependent on particular receptors existing on the luminal surface of cells (Masserini, 2013[61]). The justification for using this technique with NPs is that the cellular mechanisms already in place for transporting macromolecular cargoes may work just as well for NPs after they have been functionalized to engage with the same receptors. The cargo is then processed by several intracellular organelle pathways to the appropriate recycling, degradation, or transcytosis to the contralateral side (Lombardo et al., 2020[59]; Teleanu et al., 2018[97]). It is anticipated that by identifying and studying novel receptors that may be employed for receptor-dependent endocytosis, more efficient brain medication delivery systems will be produced because these absorption techniques are largely resistant to lysosomal degradation (Sukanya and Arabinda, 2022[94]; Teleanu et al., 2018[97]).

Despite the fact that practically all nanomaterials belong to the BBB impermeable class, some exceptions have recently been reported. For example, gold and silica NPs have been demonstrated to enter the brain and accumulate in neurons even in the absence of any specific functionalization, with a mechanism that is largely still understood. In the case of silica, the results indicated that NPs administered to rodents via intranasal instillation entered into the brain and especially deposited in the striatum (Liu and Xu, 2022[56]; Mistretta et al., 2023[66]). According to the findings in the silica example, NPs given to animals by intranasal instillation penetrated the brain and were particularly deposited in the striatum. By using X-ray microtomography, confocal laser, and fluorescence microscopy, accurate particle distribution of gold nanoparticles in the brain was examined ex vivo. The hippocampus, the thalamus, the hypothalamus and the cerebral cortex were the places where the particles accumulated most frequently, according to the authors (Pardridge, 2016[75]).

Some types of nanocarriers may be able to move from CNS neuronal cell bodies to peripheral nerve terminals via transsynaptic retrograde transport. NPs treated with PEI and other polyplexes showed active retrograde transport via neurites, but they are unable to mediate effective biological activities once they reach the neuronal body, according to studies in this area (Liu and Xu, 2022[56]; Mohammadi et al., 2017[67]).

Neuroinflammatory disorders cause BBB degradation. The paracellular permeability of NPs can be increased by temporarily and irreversibly opening the tight junctions at the BBB and other locations. Blood-brain barrier disruption therapy, in particular, is a powerful, intensive method of administering medication to brain tumors. As a result, only NPs smaller than roughly 20 nm can use this channel to enter the brain across the BBB since tight junctions can only be opened to a certain extent (Dong, 2018[21]; Liu and Xu, 2022[56]).

This mechanism plays a critical function in the CNS in neuroinflammation, lesion formation, and brain injury in neurological illnesses such multiple sclerosis (MS) and stroke. Because anti-inflammatory medications can target the chemokines that regulate cellular trafficking and cell adhesion molecules, understanding the active periods of cell infiltration during CNS diseases is crucial. BBB crossing by immune-activated macrophages looks to offer potential plans for NP-based therapeutic developments in the future. This tactic could be implemented at least by two different ways: (1) by incorporating NPs into activated monocytes that are being employed as Trojan horses to enter the brain, and (2) by creating NPs that mimic activated monocytes (Paterson and Webster, 2016[77]; Wei et al., 2016[105]) (Figure 5(Fig. 5)).

In order to avoid RES clearance and gain longer circulation times for improved tissue uptake, nanoparticulate drug delivery devices have been utilized. However, it might be argued that increasing NPs phagocytosis by monocytes is an unconventional method of delivering medications packaged on NPs to the brain. Monocytes may act like Trojan horses and carry their cargo into the brain after phagocytosing NPs (Bakhshinejad et al., 2015[6]; Pinto et al., 2022[79]).

Drug-loaded NPs systemically delivered for therapeutic purposes must be able to bypass the immune system, overcome bodily biological barriers, and localize in target tissues. It is predictable that research on NPs that mimic immune cells may be effective in treating disorders associated with the brain and will receive a stimulus in this direction in the coming years because several studies show increased passage of monocytes across the BBB in a variety of pathological conditions (Raikwar and Jain, 2022[81]).

The current standard of care includes a careful surgical resection followed by the oral administration of temozolomide while receiving concurrent radiotherapy, however, this has not been able to significantly slow the progression of the disease (Wang and Wu, 2017[104]). New therapeutic approaches are urgently needed since primary brain tumors in adults are one of the most prevalent and lethal types (Silveira et al., 2023[91]). In recent years, polymeric nanoparticles containing the chemotherapeutic drug paclitaxel have been used by capitalizing on one of the few biological characteristics of this type of tumors that is recognized. Because of this, circulating nanoparticles containing paclitaxel may cross the BBB and build up in the tumor (Iv et al., 2015[42]; Noor et al., 2022[72]). Similar approaches, encapsulating paclitaxel with carbon nanoparticles, have been shown to improve the outcome of head and neck tumors, but again, no data on human volunteers has been demonstrated. A doxorubicin delivery method is currently being tested in human clinical trials in glioblastoma patients (Iv et al., 2015[42]; Ribarič, 2021[83]).

The main current class of drugs used in AD are acetylcholinesterase inhibitors. Another approach is to block glutamatergic neurotransmission: memantine is a NMDA-receptor antagonist (Liu et al., 2019[57]). There is obviously a need for better therapies because these treatment approaches only offer a modest improvement. However, acetylcholinesterase inhibitor (Rivastigmine) was loaded in SLN using nanotechnology in order to avoid its severe first-pass metabolism and significant side effects following oral administration. Being lipidic in nature, rivastigmine-loaded SLN demonstrated greater drug diffusion than drug solutions containing the crystalline form of the drug (Ostrom et al., 2021[74]; Zhou et al., 2013[113]). Aiming to improve their brain biodistribution, antioxidants were also loaded into SLN as a potential AD treatment. Particularly in neuronal cell lines, astaxanthin-loaded SLN demonstrated a potent neuroprotective effect against oxidative stress (Whittle et al., 2015[106]). Biodegradable polymeric nanoparticles made of polyethylene glycol that have been functionalized with certain antibodies or oligopeptide medications have been used to stop the development of amyloid fibrils, which cause the disease (Yusuf et al., 2021[111]; Zhou et al., 2013[113]).

Metallic nanoparticles have been investigated for their novel biological ability to promote cell death and induce autophagy. Moreover, biological metallic NPs are cytotoxic agents to fight different types of cancer (Hassanzadeh et al., 2017[33]). For the anticancer activity of biological NPs, there are three different mechanisms. The first is the apoptotic pathway, which depends on an elevated quantity of ROS and causes oxidative stress and DNA fragmentation in the malignant cell. Secondly, proteins and DNA interference play a crucial role in the anticancer activity of nanoparticles, as these nanomaterials can disrupt protein functions involved in cancer cell signaling, proliferation, and survival, while also interacting with DNA to induce strand breaks, inhibit replication, and impair repair mechanisms. Thirdly, the interaction of biological nanoparticles with cell membranes alters cell permeability and mitochondrial dysfunction (Bourganis et al., 2018[13]). Liposomes have been used in studies to transport anti-cancer medications including doxorubicin and erlotinib. The findings revealed a much-increased translocation across the blood-brain barrier (Chen, 2019[14]; Hasan et al., 2019[32]; Hussen et al., 2023[39], 2024[37][40]). There is an in vivo study, for instance, liposomes and polymeric nanoparticles have been used to co-encapsulate drugs like doxorubicin and paclitaxel, or chemotherapeutics with gene therapy agents. These combination therapies showed enhanced therapeutic outcomes in animal models due to the ability of nanoparticles to target specific tissues or tumors, prolong drug circulation, and co-deliver agents in a controlled manner.

While many of these studies have shown promise in vivo models, translating these findings to individualized human therapies is still in its early stages, as challenges like dosing optimization, nanoparticle stability, and long-term safety must be addressed.

Several types of nanoparticles have been explored for Parkinson's disease, which is linked to motor aspects such as rest tremor, bradykinesia, rigidity and postural instability, olfactory dysfunction, cognitive impairment, mental symptoms, and autonomic dysfunction (Bourganis et al., 2018[13]; Mendes et al., 2018[63]). Some of these researches described the use of chitosan nanoparticles for the ex vivo delivery of the Parkinson's medications, Pramipexole and Selegiline, two well-known anti-Parkinson drugs (Xiong et al., 2019[109]).

The discovery of methods for both immediate therapy and post-stroke recovery is essential because there are few treatments now available for stroke. Studies on using polymeric nanoparticles, liposomes, metal and metal oxide nanoparticles, as well as inorganic and organic nanoparticles, are currently being done for stroke therapy (Shen et al., 2017[89]; Sun et al., 2016[95]). According to one study, Lexiscan was encapsulated in poly (lactic-co-glycolic acid) nanoparticles functionalized with chlorotoxin as a target ligand that could increase blood-brain barrier permeability. Findings demonstrated increased stroke survival, demonstrating the system's potential for stroke therapy (Hussen, 2023[36]; Sood et al., 2017[93]).

Time of publication articles: Most of the articles that we used were within the last 10 years 2013-2023, we tried to choose those articles that were recently done.

Old studies that are done before 2013 are excluded.