Platinum nanoparticles (PtNPs) are being researched extensively for their potential to mitigate neurotoxicity and oxidative stress in neurological conditions. Their unique physicochemical properties, such as high surface area and catalytic activity, provide them with a capacity to scavenge ROS, reduce inflammation, and protect neuronal cells from damage that are caused by NDs, toxins, or ischemic injury. The research revealed details on how PtNPs influence brain damage, cerebral blood flow (CBF), and oxidative stress in rats subjected to ischemic conditions. Also, despite their extremely low accumulation in the brain, these nanoparticles demonstrated significant neuroprotective properties (Filippov et al., 2023). It was found that PtNPs weakened post-ischemic hypoperfusion, attenuated neuronal apoptosis with minimal cell death in the hippocampus region, and improved glutathione redox status by preserving the glutathione redox balance and reduced oxidative damage, thus modulating oxidative stress also. However, they have extremely low bioavailability as it was shown that despite their neuroprotective effects, they were found in very low concentrations in brain tissue. Such effects were mediated through indirect mechanisms and not direct accumulation in brain tissue, proving PtNPs to be a significant candidate in the quest for effective neuroprotective agents. The study reported that PtNPs could activate neuroprotective signaling pathways, including the PI3K/Akt pathway, promoting neuronal survival and reducing apoptosis in neuronal cultures exposed to ischemic conditions. This suggests a promising avenue for therapeutic use in stroke and other ischemic brain injuries. Another study explored the neuroprotective potential of PtNPs that were synthesized from Biophytum reinwardtii in a zebrafish model of PD (Bandaru et al., 2024a). The disease was induced by MPTP and the zebrafish were treated with different concentrations of these nanoparticles. The effects on locomotor activity, oxidative stress markers, and catecholamine levels were assessed and the results showed that PtNPs significantly improved movement, increased antioxidant levels, and restored catecholamine balance, suggesting their potential for neuroprotection in PD. These findings highlight the potential of platinum nanoparticles in treating acute cerebrovascular disorders through systemic antioxidant and neuroprotective pathways. Given their unique properties to bring about antioxidant, anti-inflammatory, and electrochemical changes, PtNPs are gaining much traction in neurodegenerative disease research as well. They can act as nanozymes and ROS scavenging molecules in neurovascular units, where even as 5 nm sized particles, they can act as antioxidant enzyme-mimics that can efficiently mime the natural enzymes like catalase and superoxide dismutase. The PtNPs scavenged ROS in neurovascular cellular models, effectively protecting neurons and glial cells from oxidative damage. The impetus behind neurodegenerative cascades in conditions such as Alzheimer’s and Parkinson’s often stems from oxidative damage to vulnerable neural and glial cells (Tarricone et al., 2023). It was observed that upon administration of PtNPs, the catalytic properties of the nanozyme activated the lysosomal environment, turning it into tiny, intracellular ‘microreactors’ that lowered mitochondrial stress, thus preserving the BBB integrity. When tested under kainic acid-induced excitotoxic conditions that are a proxy for neurodegeneration in an ex vivo rat hippocampal model, PtNPs showed no particular impairment of neuronal viability in CA1 and CA3 regions (parts of hippocampus), even under pathological stress. However, it was observed that they triggered microglial activation, clearly proposing an immune-modulatory role. This points to the possibility of harnessing PtNPs for therapeutic applications with controlled dosing (Gulino et al., 2021). Another study in a rat model showed that electrodes coated with PtNP (used for deep brain stimulation) displayed reduced and stabilized impedance over 4 weeks of stimulation. This result points to the possibility of enhanced precision and longevity of neurostimulation therapies for Parkinson’s and other movement disorders, indicating PtNPs’ utility in neuroelectronic interfaces (Angelov et al., 2024).

Titanium dioxide nanoparticles (TiO₂ NPs) are widely used in consumer products. However, they are being explored in therapeutic uses as well. Even though the neurotoxic effects of TiO₂ have raised concerns due to their environmental presence (Aschner et al., 2023) and human exposure, it is highlighted that TiO₂, when in nanoform, can cross the BBB. The exact mechanism of how TiO₂ NPs cross the BBB is still unclear, but it is understood that once in the brain, it can induce oxidative stress and neuroinflammation, leading to disruption in brain biochemistry, followed by neuronal damage. This may influence behavioural disorders and neurodegenerative diseases, including PD. The neurotoxic potential of TiO₂ NPs is influenced by the physicochemical properties and how they are exposed to the site of action during disease conditions. Another study investigated the neurotoxic effects of TiO₂ NPs on neuronal, PC-12 cells. The study mainly focused on cytotoxicity, dopaminergic gene expression, and acetylcholinesterase inhibition. When two differently sized nanoparticles (10 nm and 22 nm) along with polyvinylpyrrolidone (PVP)-coated TiO₂ NPs were used for the study, it was observed that at concentrations ≥10 μg/mL, it induced dose-dependent cytotoxicity due to increased ROS and nitrogen species (Suthar et al., 2023). Elevated inflammatory markers (like IL-6 and TNF-α), mitochondrial dysfunction, and apoptosis-related caspase-3 activation were observed, accompanied by acetylcholinesterase inhibition. These results suggest a potential neurochemical disruption in the brain. However, dopaminergic gene expression remained unaffected at lower exposure levels, which was considered an interesting observation. The surface coating of the nanoparticles with PVP reduced neurotoxic effects, highlighting its potential for safer medical applications. In vitro studies using neuronal and glial cell lines revealed that TiO₂ NPs can induce neuronal cell damage through the induction of oxidative damage via the generation of ROS. It was also found that the cells encounter reduced ATP levels invoked by mitochondrial dysfunction. An exceptionally high dose or prolonged exposure to TiO₂ NPs has been shown to trigger apoptosis/necrosis (Song et al., 2015). Further, specific inflammatory responses were observed with microglial activation and increased expression of pro-inflammatory cytokines (like IL-6, TNF-α), specifying role for TiO₂ NPs in neuroinflammation - a key driver in diseases like Alzheimer’s and Parkinson’s. When applied to in vivo rodent models via inhalation or intravenous routes, the TiO₂ NPs were found to be accumulated in various regions of the brain, including the hippocampus and cortex. Behavioral assays were conducted in the test organism, which revealed specific impairment of spatial memory and learning, consequently correlating with histopathological changes in brain tissue. Evidence of BBB disruption was observed, further facilitating the entry of other neurotoxicants. Assays on neurodevelopmental impact through prenatal exposure in these models showed altered brain development, pointing to potential risks during gestational periods (Zhang, Song et al., 2023).

The neuroprotective effects of gold nanoparticles (AuNPs) have been extensively studied for the treatment of PD. The nanoparticles were found to inhibit the generation of ROS and modulate the expression of pro-apoptotic and anti-apoptotic proteins (Piktel et al., 2021), suggesting that AuNPs have the potential to serve as a therapeutic agent in neurodegenerative diseases, including PD (de Bem Silveira et al., 2021). AuNPs are known to mitigate neuronal apoptosis that is caused by glutamate toxicity, which is considered a key factor in neurodegenerative diseases. Glutamate is an excitatory neurotransmitter, and its presence can lead to excessive calcium influx triggering oxidative stress, mitochondrial dysfunction, and caspase activation, ultimately resulting in neuronal cell death. It was inferred from the study that AuNPs reduced oxidative stress by scavenging ROS, and stabilized mitochondrial function by preventing the release of cytochrome c. It was found to inhibit the activation of caspase-3, strengthening its role in induction of apoptosis. It was also found to modulate neuroinflammatory pathways by reducing inflammatory cytokines. All these protective roles highlight the potential of AuNPs as therapeutic agents for neurodegenerative conditions like AD and PD (de Bem Silveira et al., 2021; Chiang et al., 2024). Further, the potential of AuNPs in diagnosing and treating neurodegenerative diseases were studied. It was understood that AuNPs could be functionalized to explicitly target the key pathological markers of neurodegenerative diseases - Tau and α-synuclein proteins. AuNPs enabled the detection of these proteins even at low concentrations in biological samples like blood or cerebrospinal fluid, enabling early and accurate diagnosis of the disease. AuNPs can also serve as drug delivery platforms, enabling the transport of therapeutic agents directly into the brain, thus improving treatment precision while maintaining minimal side effects (Tapia-Arellano et al., 2024). However, while the use of AuNPs looks promising, safety and biocompatibility are major concerns, requiring rigorous preclinical and clinical studies before widespread medical use. In vitro assays revealed the neuroprotective effect of AuNPs through anti-inflammatory activity, where supplementing the cultured microglial cells with AuNPs reduced neuroinflammation, as evidenced by the downregulation of pro-inflammatory cytokines like TNF-α and IL-6. These are generally elevated in AD and PD pathology (Chiang et al., 2024). Targeting of Tau and α-synuclein by functionalized AuNPs revealed a selective binding of the NPs to misfolded proteins (Tau in AD and α-synuclein in PD), thereby inhibiting their aggregation and toxicity in the tested neuronal cells (Tapia-Arellano, 2024). Treatment with AuNPs also revealed the antioxidant properties, where ROS was scavenged to protect the neurons from oxidative damage - a key driver in neurodegeneration. In vivo studies in mouse models showed that when conjugated with therapeutic agents, AuNPs improved cognitive function with reduced amyloid plaque burden. Drug delivery across the BBB was also observed to increase bioavailability in the brain. When targeted towards α-synuclein aggregates, AuNPs reduced motor deficits and neuroinflammation in PD animal models. This ability of AuNPs to deliver neuroprotective compounds directly to the regions of the brain that are affected by PD or other neurodegenerative conditions revealed improved therapeutic outcomes. AuNPs have even been helpful to mitigate ischemic damage after stroke – they act by reducing oxidative stress and inflammation, thereby preserving the integrity of neuronal cells, providing cerebrovascular protection (Chiang et al., 2024).

Oxidative stress followed by dopaminergic neuron damage and protein misfolding are considered as major contributors to neurodegeneration. The neuroprotective potential of selenium nanoparticles (SeNPs) in treating PD was explored (Umapathy et al., 2024; Kalčec et al., 2023). SeNPs are found to act as antioxidants, scavenging the ROS and reducing oxidative damage. They also help in maintaining mitochondrial integrity by preventing cytochrome c release and apoptosis, which are crucial for neuronal survival. SeNPs are known to cross the BBB as any other nanoparticles and therefore, targeted delivery of SeNPs to affected regions of the brain are possible. SeNPs also suppress neuroinflammation by lowering the levels of pro-inflammatory cytokines like IL-6 and TNF-α, which significantly contribute to PD progression. The accumulation of misfolded proteins like α-synuclein and tau are inhibited by SeNPs. All these results point to the fact that SeNPs could be used as a potential therapeutic agent in neurodegenerative diseases like Parkinson’s (Umapathy et al., 2024).

Another research also discussed the potential of SeNPs for use as a mode of delivery for transporting drugs to treat PD. Since PD is characterized by dopaminergic neuron degeneration, the mode of action of SeNPs in enhancing drug transport across BBB was investigated and the therapeutic efficacy was also examined. It was understood that when SeNPs were functionalized with PVP and polysorbate 20 (Tween), it improved stability and drug-binding capacity. Also, L-DOPA and dopamine were successfully loaded onto SeNPs, showing that they have strong binding interactions that could enhance drug delivery. SeNPs also improved BBB permeability, allowing better drug absorption in brain cells, which is important in treatment of diseases like PD. Further, in vitro studies demonstrated efficient drug uptake by human brain endothelial cells (Kalčec et al., 2023). The antioxidant, anti-inflammatory, and neuroprotective properties of SeNP in both in vitro and in vivo studies provided compelling evidence of their therapeutic potential, especially in neurodegenerative disease conditions like AD, PD, and amyotrophic lateral sclerosis (ALS). Assays with the in vitro neuronal cell cultures revealed that the treatment with SeNPs reduced β-amyloid aggregation and inhibited tau hyperphosphorylation, which are the hallmarks of neurodegenerative diseases. The modulation of neuroinflammation through the downregulation of pro-inflammatory cytokines (e.g., IL-1β, TNF-α) in microglial cells indicated the ability of SeNPs to suppress neuroinflammatory cascades (Vicente-Zurdo et al., 2024). In vivo evidence in AD mouse models (transgenic AD mice treated with SeNP) revealed improved cognitive performance mediated by behavioral tests. It showed reduced amyloid plaque burden in the hippocampus, and enhanced antioxidant enzyme activity through glutathione peroxidase activity. When administered in PD-induced rodents, SeNPs showed protection of dopaminergic neurons in the substantia nigra with improved motor coordination and reduced tremors. They also lowered neuroinflammation markers, suggesting disease-modifying potential for the SeNPs. Further, functionalized SeNPs demonstrated the ability to cross the BBB, thereby delivering the therapeutic payloads directly to affected regions of the brain (Rajeshkumar et al., 2019).

The neuroprotective effects of magnetite nanoparticles (Fe₃O₄ NPs) were explored and it was found that they exhibited significant ability to reduce oxidative stress (Ucar et al., 2022), modulate neuroinflammation (Tamjid et al., 2023), and support mitochondrial function (Zhang et al., 2021b). These abilities of magnetite nanoparticles help the brain to preserve dopaminergic neurons in neurodegenerative diseases like Parkinson’s and Alzheimer’s. The potential of magnetite nanoparticles to act as drug-delivery systems was reviewed and it was discerned that the magnetite nanoparticles served as excellent agents for targeted therapy, improving treatment efficiency while minimizing systemic side effects. Research on the neuroprotective potential of Fe₃O₄ NPs in a PD model, focused on their ability to enhance neuronal survival, and improve motor function. Improved mitochondrial functions were observed, leading to enhanced energy metabolism and reduced apoptosis. They were found to modulate neuroinflammatory pathways by lowering levels of pro-inflammatory cytokines like IL-6 and TNF-α. Enhanced drug delivery potential suggested that Fe₃O₄ NPs could be used as carriers for targeted PD therapy (Khadrawy et al., 2024). Another study investigated the neuroprotective potential of iron oxide nanoparticles (IONPs) synthesized through green-route via ascorbic acid (AA-IONPs) in PD using both in vitro and in vivo models. The AA-IONPs were found to reduce neuroinflammation by lowering the levels of nitric oxide, prostaglandin E2, IL-6, and IL-1 in murine microglial BV2 cells. In vivo experiments on PD-induced C57BL/6 mice demonstrated enhanced motor coordination and reduced neuroinflammation after AA-IONP treatment. These findings suggest that AA-IONPs could serve as an effective nano-drug for neuroprotection through their anti-inflammatory and antioxidant properties (Li et al., 2023). The neuroprotective effects of IONPs in a PD model were studied (Khadrawy et al., 2024). The findings indicated that these nanoparticles could effectively deliver curcumin and enhance its bioavailability in neuronal cells. They not only demonstrated antioxidant activity but also modulated neuroinflammation by reducing the levels of inflammatory cytokines, providing a dual mechanism of action. In AD imaging, Fe₃O₄ NPs have been used as MRI contrast agents for the early detection of AD (Ulanova et al., 2020). The magnetic properties of Fe₃O₄ NPs enhance the resolution of the images to such an extent that when functionalized with imaging molecules, they can target amyloid plaques. Neuroprotective signaling in rodent models showed that Fe₃O₄ NPs activated the neuroprotective pathways and supported mitochondrial function, thereby reducing apoptosis and maintaining neuronal viability (Abdelmonem, et al., 2024).

Silica nanoparticles (SiNPs) have been studied for their ability to deliver therapeutic agents across the BBB (Bhatane et al., 2023). The potential of functionalized SiNPs as drug-delivery systems for neuroprotective treatments was examined and it was found that they enhanced the cognitive function in neurodegenerative diseases like PD. When SiNPs were functionalized with targeting ligands, they improved the BBB penetration and it brought about precise drug delivery to neuronal tissues. When neuroprotective drugs were loaded onto SiNPs, it also ensured sustained therapeutic effects through enhanced stability and bioavailability. Further, in vitro and in vivo studies with SiNPs demonstrated reduced oxidative stress, improved neuronal survival, and enhanced cognitive function in disease models. They also minimized systemic toxicity, making them a promising biocompatible nanocarrier for neurological treatments. Since mesoporous SiNPs offer high surface area and tunable pore size, they are ideal for targeted drug delivery. They protect encapsulated drugs from premature metabolism, ensuring controlled release and stability. They are further explored for treating brain tumors, epilepsy, depression, and multiple sclerosis as their biocompatibility and surface conjugation enhance therapeutic efficacy while minimizing side effects (Bhatane et al., 2023). When used as nanocarrier system, they showed high biocompatibility and low toxicity, indicating its potential use in neuroprotection strategies. In vitro studies on SH-SY5Y (human neuroblastoma) cell model revealed that exposure to SiNPs induced excessive ROS generation, Ca²⁺ overload, and mitochondrial dysfunction. They were shown to activate both parthanatos and caspase-dependent apoptotic pathways, subsequently leading to neuronal cell death (Ma et al., 2025). However, when the cells were treated with Olaparib, a PARP inhibitor and Z-VAD, a caspase inhibitor, these observed effects were significantly mitigated, suggesting a potential for controlled therapeutic modulation. Further, functionalized SiNPs were shown to promote α-synuclein aggregation in dopaminergic neurons, thus mimicking Parkinson’s pathology. This highlights both the diagnostic potential (by modelling disease mechanisms) and the need for surface modification strategies to reduce neurotoxicity. In A53T transgenic mouse model, the intranasal administration of SiNPs led to the hyperphosphorylation and aggregation of α-synuclein, mitochondrial impairment, oxidative stress, dysfunction of autophagy and neuronal apoptosis. This is a clear indication of the penetrative effect of SiNPs on the CNS, resulting in potential for targeted therapeutic delivery in PD-like pathological conditions. Neurodevelopmental toxicity studies showed that prenatal exposure to SiNPs altered brain development in rodent models, emphasizing the importance of dose control and timing in therapeutic applications (Yang et al., 2022; Ma et al., 2025).

The neuroprotective potential of nano-graphene oxide (NGO) in combating PD was tested by targeting ROS scavenging and anti-inflammatory mechanisms. It was found that NGOs affected SH-SY5Y cells and a 6-hydroxydopamine (6-OHDA)-induced Parkinsonian rat model - it protected the tested cells against 6-OHDA-induced toxicity by reducing oxidative stress. It also suppressed microglial activation, which is linked to neuroinflammation in PD. In the rat models tested, NGO was found to have improved akinesia symptoms and reduced contralateral rotations in response to apomorphine, which implied neuroprotection through increased tyrosine hydroxylase-positive cells in NGO-treated rats, suggesting preservation of dopaminergic neurons. Overall, the study presented NGO as a promising candidate for PD treatment (Kim et al., 2023a). While discussing the neuroprotective effects of graphene-based nanoparticles, it was apparent that they can influence many molecular events that contribute to PD neurodegeneration like autophagy, inflammation, and oxidative stress. They are explored for their role in interventions related to nanomedicine and regenerative approaches to restore neuronal function and was believed to improve early-stage PD detection through graphene-based biosensors (Oz et al., 2023). When exploring the therapeutic potential of graphene nanoparticles, a study was conducted to check how graphene oxide (GO) nanoflakes could target dysfunctional synaptic plasticity in the amygdala, particularly in conditions like post-traumatic stress disorder (PTSD). By selectively targeting glutamatergic synapses, it was found that GO nanoflakes with small lateral dimensions (s-GO) could transiently interact with glutamatergic synapses in the hippocampus, reducing neurotransmitter release. This was of specific significance as PTSD is linked to hyperactive glutamatergic transmission in the lateral amygdala (LA). The study further investigated whether s-GO can modulate this excessive activity to restore normal synaptic function and examined the subcellular targets of s-GO and its interaction with potentiated synapses, potentially reducing long-term potentiation (LTP) associated with PTSD. The study also explored s-GO as a nanocarrier for drug delivery, using neuropeptide Y (NPY) as a biologically active molecule to enhance therapeutic effects (Pati, 2022). The promising role of graphene oxide nanoparticles in neuroprotection were highlighted and their ability to promote neuronal differentiation makes it a compelling candidate for regenerative therapies in neurodegenerative diseases.

The antioxidant, anti-inflammatory, and neuroprotective properties of silver nanoparticles (AgNPs) have made them a promising candidate in neurodegenerative disease control. A particular study highlighted the neuroprotective potential of AgNPs synthesized using a red pigment from Streptomyces sp. A23, isolated from Algerian bee pollen on SH-SY5Y cells and their potential therapeutic applications (Mohamed et al., 2025). The sample was tested at concentrations of 2, 4, and 8 μg/mL, showing cytotoxic effects on the experimental cells. Significant neuroprotective activity of AgNPs was evident even at lower concentrations (1 mM, pH 7), where a dose-dependent effect was noted. The study also indicated that AgNPs induced their neuroprotective activity through mitigation of oxidative stress, which is a major contributor to the progression of neurodegenerative diseases. These findings suggested that AgNPs synthesized using Streptomyces sp. A23 could be used as a promising neuroprotective agent. However, the authors are of the opinion that it warrants further investigation for use as a drug for PD, AD, and other neurodegenerative disorders. AgNPs are known to cause significant neuronal death. This has raised serious concerns about their long-term safety. Research suggests that AgNPs can cross the BBB and accumulate in the brain, leading to neurotoxicity and neuronal degeneration (Janzadeh et al., 2022). While AgNPs hold potential for neuroprotection, their toxicity risks must also be carefully assessed and managed to ensure safe and effective applications in neurodegenerative disease treatment. Since neurodegenerative diseases like Parkinson’s already involves progressive neuronal loss, AgNP-induced neuronal death could worsen disease progression rather than help. AgNPs are also found to be linked to microglial activation, which may exacerbate neuroinflammation. All these indicate that AgNPs can damage synaptic structures, potentially impairing cognitive and motor functions. Such research underscores the potential dangers of AgNP exposure, urging caution in their biomedical applications.

Nanoparticles derived from chitosan, a biodegradable and biocompatible polysaccharide obtained from chitin (which is found in the exoskeletons of crustaceans) are called chitosan nanoparticles (CsNPs). These types of nanoparticles have gained significant attention in neuroscience, particularly in addressing neurodegenerative diseases. They have unique physicochemical properties, like high permeability across biological barriers, low toxicity, and inherent antioxidant and anti-inflammatory effects which make them promising candidates for drug delivery systems in neurodegeneration. The neuroprotective potential of CsNPs as carriers for Ginkgo biloba extract (GBE), specifically targeting oxidative stress-induced damage in SH-SY5Y cells were examined (Karavelioglu and Cakir-Koc, 2021) and it was understood that these nanoparticles enhanced neuroprotection through improved bioavailability and increasing cell viability from 60% to 92.3%. It was revealed that GBE-loaded CsNPs effectively scavenged ROS, thereby reducing oxidative damage in neuronal cells. The ionic gelation method used for CsNP synthesis resulted in high encapsulation efficiency (97.4%) and ensured controlled release and better cellular uptake. These findings suggested that GBE-CsNPs could be developed as food supplements or therapeutic agents for conditions like AD and PD. Further, studies have shown the neuroprotective potential of CsNPs, improving outcomes in animal models of neurodegeneration and neuroinflammation. The potential of CsNPs as a therapeutic channel for neurological disorders were explored, and the ease of functionalization make these nanoparticles promising candidates for drug delivery in neurodegenerative diseases like Alzheimer’s, Parkinson’s, epilepsy, migraine, psychotic disorders, and brain tumors (Vahab et al., 2024). CsNPs help overcome the BBB by enhancing drug absorption, protecting drugs from degradation, and enabling targeted delivery. Additionally, it was observed that surface modifications of CsNPs allow for the attachment of specific ligands or molecules, improving precision in drug delivery to neuronal cells. However, despite these advancements, challenges remain in large-scale production, regulatory approvals, and long-term safety issues that need to be addressed for the future use of CsNP-based therapies in neurological disorders.

By encapsulating multiple neuroprotective agents, polymeric nanoparticles can modulate immune responses and even promote neuronal regeneration by providing multifunctional therapeutic benefits. By functionalizing with specific ligands, these nanoparticles can improve targeted drug delivery to damaged neurons. The polymeric nanoparticle-based therapies offer a revolutionary shift in precision medicine, with better drug absorption, enhanced cellular targeting, and potentially reduced side effects. Many researchers use polymeric nanoparticles to encapsulate neuroprotective compounds and deliver them to the site of action. For example, the stability and bioavailability of curcumin, a natural compound was significantly improved when encapsulated in a polymeric substance. The specially formulated, curcumin-loaded nanoparticles significantly reduced amyloid-beta plaque accumulation and inflammation, showcasing the potential of nanotechnology to enhance the therapeutic effects of existing compounds (Pei et al., 2024). Another study explored the neuroprotective potential of edaravone-loaded mPEG-b-PLGA polymeric nanoparticles in an in vitro ischemia model using the SH-SY5Y cell line. It was observed that the polymeric encapsulation improved edaravone’s bioavailability and stability and considerably lowered the activities of ROS and nitric oxide (NO), which are major contributors to neuronal damage. The expression of pro-apoptotic gene Bax was downregulated while the anti-apoptotic genes HSP70 and Bcl-2 were upregulated, promoting cell survival. Improved neuroprotection was observed where the cells treated with edaravone-loaded nanoparticles showed better resistance to ischemia-induced damage compared to free edaravone (EDV). By enhancing edaravone’s therapeutic effects, these nanoparticles could pave the way for more effective neuroprotective strategies in stroke and other neurodegenerative conditions (Sharifyrad et al., 2022).

Spinal cord injury (SCI) leads to progressive neuronal damage, driven mainly by oxidative stress and inflammation. In such cases, the ROS-scavenging were used for neuroprotection to mitigate oxidative stress and inflammation (Zhang et al., 2021a). These nanoparticles offer a promising therapeutic strategy by reducing secondary injury, potentially improving recovery outcomes. The lipid nanoparticles effectively neutralized harmful free radicals, reducing oxidative damage in injured spinal cord tissue. They also suppressed the secretion of pro-inflammatory cytokines (such as IL-1β, TNF-α, and IL-6), helping to control inflammation. Targeted accumulation of the nanoparticles at the injury site enhanced their therapeutic effects. Functional recovery was observed in animal models, where treatment with these nanoparticles led to better axonal protection and improved motor function.

RNA therapies, including messenger RNA (mRNA) and siRNA, offer promising approaches for gene silencing and protein expression in neurodegenerative diseases. The mRNA, siRNA and antisense oligonucleotides (ASOs) can correct genetic defects, silence harmful genes, or restore normal protein function (Lee et al., 2022). A cutting-edge study concentrated on lipid-based nanoparticles that served as efficient RNA carriers, protecting RNA from degradation and enhancing its delivery across the BBB. Various types of lipid-based platforms include liposomes, lipoplexes, solid lipid nanoparticles (SLNPs), lipid nanoparticles (LNPs), nanoemulsions (NEs), nanoliposomes, nanophytosomes, and nanostructured lipid carriers (NLCs), each with unique properties for targeting the CNS (Tsakiri et al., 2022). Surface modifications of LNPs improve target specificity, allowing RNA therapies to reach affected neurons more effectively. This strategy is based on LNPs as carriers for RNA-based therapeutics in neuroprotection. The delivery of siRNA targeting neurotoxic pathways in models of amyloid-beta toxicity was studied and the results indicated that LNPs improved the uptake of siRNA by neuronal cells, leading to a significant reduction in neurotoxic effects and suggesting potential therapeutic applications in neurodegenerative diseases. Thus, lipid-based nanoparticles are emerging as a powerful tool for treating neurodegenerative diseases by enhancing drug delivery, reducing toxicity, and improving therapeutic efficacy (Fernandes et al., 2021).

Hybrid nanoparticles that integrate different materials like polymers, lipids, metals, and biocompatible nanomaterials are emerging as a promising approach by offering enhanced therapeutic capabilities for treating neurological disorders. These hybrid systems can leverage the unique properties of each component to optimize drug delivery, whereby they can reduce toxicity, and improve brain targeting. Their additional ability to cross the BBB and deliver antioxidants, anti-inflammatory agents, and neurotrophic factors make them valuable candidates for mitigating neurodegeneration in most of the neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, and stroke-induced brain injury. Further, the multifunctionality of hybrid nanoparticles allows for controlled drug release, improved cellular uptake, and enhanced neuroprotective effects, making them superior to its conventional counterpart, namely, single-material nanocarriers (Kumar and Kumar 2024). Many of the research with hybrid nanoparticles have shown that combining lipid-based carriers with polymeric shells or metallic cores can significantly boost drug stability, bioavailability, and therapeutic efficacy. These advanced systems not only protect neurons from oxidative stress and inflammation but also promote neuronal regeneration, offering new possibilities for treating CNS disorders. While investigating the therapeutic potential of a polymer/lipid hybrid nanoparticle (PLHNPs) loaded with quetiapine fumarate (QF) in a cuprizone-induced schizophrenia model in mice, the drug delivery efficiency and behavioral and neurological outcomes in schizophrenia were revealed. Further, the hybrid nanoparticles demonstrated high entrapment efficiency (99.68%) and a sustained release profile, with 95% of QF released over 28 days. Moreover, mice treated with the optimized hydrogel-based formulation (HF-G3) showed significant recovery from schizophrenia-like symptoms, compared to untreated cuprizone-fed mice. This was a significant study that revealed reduced levels of pro-inflammatory cytokines (TNF-α, IL-1β), gamma-aminobutyric acid (GABA), and glial fibrillary acidic protein (GFAP), indicating reduced neuroinflammation and improved neuronal integrity of the formulation (Elkasabgy et al., 2023). In addition to this, the study ensured that intramuscular administration prolonged therapeutic effects, reducing the need for frequent dosing. Generally, quetiapine fumarate has very low oral bioavailability (9%) and the study successfully demonstrated the potential of PLHNPs in sustained drug delivery, even in case of drugs with very low bioavailability.

Auranofin is an orally administered gold compound primarily used to treat rheumatoid arthritis, but recently, it has been studied for neuroprotective effects, particularly in PD models, where it helps reduce oxidative stress and neuroinflammation (Soni et al., 2025). The ability of auranofin-loaded chitosan-lipid hybrid nanoparticles (AUF-CLHNPs) to modulate GSK-3β/Nrf2/HO-1 signaling pathways in a rotenone-induced PD model was studied and it was found that AUF-CLHNPs significantly improved auranofin’s brain penetration, overcoming its limited natural bioavailability. The hybrid nanoparticles were found to restore motor function by reducing oxidative stress, and protecting the dopaminergic neurons in the substantia nigra, a key brain region affected in PD. The anti-inflammatory responses were influenced where UF-CLHNPs phosphorylated GSK-3β, leading to upregulation of Nrf2/HO-1, affecting oxidative pathway as well. The pro-inflammatory cytokine levels (TNF-α, IL-1β) were downregulated and neuronal integrity was restored. Thus, the study successfully demonstrated the use of a novel drug delivery approach that enhanced auranofin’s therapeutic efficacy in PD. The hybrid nanoparticle formulation ensures sustained drug release, improving treatment outcomes.

The exceptional physicochemical properties of two-dimensional (2-D) materials made them promising candidates for the diagnosis and treatment of neurodegenerative diseases and recently, they gained immense attention in biomedical research due to these properties. Some of these materials like graphene, transition metal dichalcogenides (TMDCs), molybdenum and black phosphorus, exhibit high surface area, excellent biocompatibility, and tunable electronic characteristics, which enhance their interactions with biological systems. In the field of diagnostics, 2-D materials can be integrated into biosensors for highly sensitive and selective detection of biomarkers associated with conditions like AD and PD (Wu et al., 2021). Additionally, their unique optical, electrical, and magnetic properties enable early disease detection through techniques such as fluorescence imaging, electrochemical sensing, and MRI enhancement. However, 2-D materials are of assistance beyond diagnosis as they are valuable in neuroprotective therapies as well. The targeted delivery of neuroprotective agents across the BBB is mainly attributed to their increased drug-loading capacity and controlled release mechanisms. This is based on the principle of increasing treatment efficacy while minimizing systemic side effects. The antioxidant and anti-inflammatory activities also affect the intrinsic neuroprotective properties, which help in mitigating oxidative damage and neuroinflammation that are considered as two main drivers of neurodegeneration (Lee et al., 2020). The ongoing advancements in the field of 2-D materials for neurodegenerative therapies hold great potential to revolutionize precision medicine as they can be more efficient, targeted, and less invasive than other conventional therapeutic strategies. For example, the therapeutic potential of the nano-bio interactions of 2-D molybdenum disulfide (MoS₂), an ultrathin nanomaterial, is being explored. It is observed that 2-D MoS₂ maintains high anisotropy, surface-to-volume ratio, chemical functionality, and mechanical strength which makes MoS₂ a promising material for biomedical applications, including drug delivery, regenerative medicine, biosensing, and bioelectronics (Yadav et al., 2019; Jin et al., 2025). MoS₂ interacts with biological systems, influencing the intracellular trafficking, biodistribution, and biodegradation of therapeutic drugs. MoS₂ is also found to interact with proteins and specific cell types, such as immune cells and progenitor stem cells, which determine its short-term and long-term biocompatibility (Roy et al., 2022). Also, 2-D MoS₂ belong to the TMDCs that can contribute to neuroprotection by mimicking biological synapses and neurons, enhancing neuronal plasticity and repair. Their high surface reactivity and tunable electronic properties allow them to interact with neural networks, supporting synaptic modulation and neuroregeneration. Research suggests that TMDC-based neuromorphic devices can help reduce oxidative stress and neuroinflammation, two major contributors to neurodegenerative diseases. By facilitating efficient signal transmission and memory retention, these materials may aid in cognitive restoration and neural repair (Ma et al., 2023). These TMDCs can be employed to make flexible neuromorphic devices that contribute to neuroprotection by mimicking biological synapses and neurons. These devices offer high adaptability and plasticity, making them promising for brain-machine interfaces and neural repair technologies (Ke et al., 2024; Ma et al., 2023). Some of the modes of PD modulation by 2-D materials are represented in Figure 5.

Exosomes are naturally occurring nanoscale vesicles derived from specific cells (Figure 6) that can facilitate drug delivery while being biocompatible and biodegradable and therefore, demonstrate a promising role in gene therapy for neurodegenerative disorders. The neuroprotective role of exosomes in CNS injuries, including traumatic brain injury (TBI), SCI, and subarachnoid hemorrhage (SAH) was studied and it was found that they help to restore cognitive abilities by facilitating neuronal repair and synaptic plasticity, thereby improving cognitive function. They are also known to regulate immune responses, minimizing neuroinflammation by suppressing the reactions. Further, they aid in neuroprotection by influencing cellular recycling mechanisms (autophagy regulation) and inhibiting cell death pathways (anti-apoptotic effect), subsequently reducing neuronal loss. They also help in maintaining BBB integrity and offering BBB protection and prevention of further damage. The key molecular mechanisms through which exosomes exert their neuroprotective effects are the microRNA (miRNA), NF-κB, PI3K/AKT, Notch1, and ERK pathways, among others (Zhang et al., 2022). Exosomes derived from glial cells can exert both neuroprotective and neurotoxic effects, depending on the cellular environment and molecular cargo they carry (Figure 7). When derived from astrocytes and oligodendrocytes, these exosomes can modulate synaptic plasticity by enhancing neuronal communication (Akbari-Gharalari et al., 2024). They accomplish this task by delivering neurotrophic factors that support synaptic signals and connections, and help in repair through macromolecules like nucleic acids and sugars. Exosomes help in the regulation of immune responses by carrying anti-inflammatory cytokines, especially by reducing neuroinflammation in conditions like AD and PD. Another mechanism of action is the transport of antioxidant enzymes that help to neutralize ROS, preventing neuronal damage. By delivering tight junction proteins, they strengthen the BBB, thereby preventing harmful substances from entering the brain (Heidarzadeh et al., 2021). Exosomes are also found to regulate autophagy by influencing cellular recycling mechanisms, and promoting the clearance of misfolded proteins associated with neurodegenerative diseases. More mechanisms of action are detailed in Figure 8. However, at times, exosomes are found to have neurotoxicity, particularly those from activated microglia that can carry pro-inflammatory cytokines, exacerbating neuroinflammation and contributing to neuronal damage. When they facilitate the intercellular transfer of misfolded proteins, such as amyloid-beta and tau, they are known to accelerate disease progression in Alzheimer’s, instead of retarding the condition. They may also contribute to further neurodegeneration as they tend to carry damaged mitochondrial components that can impair energy production. The dual role of exosome (neuroprotection and neurotoxicity) is further reinforced by the role they play in activating cell death pathways by affecting apoptotic signals, increasing neuronal apoptosis in pathological conditions (Oyarce et al., 2022).

Nanogels are cross-linked polymeric networks that can swell in response to environmental stimuli, providing controlled drug release. They have high potential to serve as advanced drug delivery systems for CNS therapeutics. Due to their hydrophilic and crosslinked polymeric networks, they can offer high drug-loading capacity, controlled release, and enhanced BBB penetration (Manimaran et al., 2023). They are highly stable and compatible with biomolecules and therefore can encapsulate neuroprotective agents while maintaining their structural integrity. They enable sustained and targeted delivery, reducing side effects. They also improve drug transport across the BBB, a major challenge in CNS treatments. Nanogels are stimuli-responsive and so, they can be designed to respond to pH, temperature, or enzymatic activity, ensuring precise drug delivery. They can facilitate cellular uptake and intracellular trafficking for efficient drug absorption by neurons and glial cells. Nanogels are being explored for Alzheimer’s, Parkinson’s, and multiple sclerosis treatments as they help to reduce neuroinflammation and promote neuronal repair (Devassy et al., 2023). The neuroprotective potential of EDV can be enhanced by preparing a glutathione (GSH)-conjugated poly (methacrylic acid) nanogel, which enhances targeted brain drug delivery. This incorporation of EDV in the nanogel is supposed to ensure drug stability, controlled release, and BBB penetration, ensuring efficient neuroprotection. Studies have also demonstrated that this nanocarrier system significantly reduced oxidative stress, enhanced cognitive function, and promoted neuronal survival in ischemic conditions (Mozafari et al., 2023).

Many of the recent studies illustrate the rapid advancement in nanotechnology for neuroprotection, incorporating innovative materials and methodologies that enhance targeting, delivery, and thus offering neuroprotective functions (González et al., 2021; Waris et al., 2022; Nayab et al., 2023). Examples of some nanoparticles delivered via nanostructures to restore homeostasis in the neuronal regions in CNS, are explained in Table 2. The nanostructure type, mechanism of action, and key findings are explained. The exploration of various nanomaterials continues to hold promise for effective interventions in neurodegenerative diseases and related neurological conditions. As research progresses, the focus on safety, biocompatibility, and translation into clinical applications remains paramount.

One of the most effective strategies for enhancing drug delivery across the BBB involves the chemical modification of therapeutic agents or the design of nanocarriers (Wu et al., 2023). This is made possible through the inclusion of lipophilic or small-molecule drugs that can readily diffuse through the BBB. Additionally, extremely small particles (like the nanoparticles) can be engineered to improve their brain-targeting capabilities. For instance, liposomes and polymeric nanoparticles when modified with specific ligands like transferrin, folate, or peptides can bind to receptors that are on the surface of endothelial cells (Mojarad-Jabali et al., 2022). These modifications will eventually facilitate receptor-mediated endocytosis, allowing nanoparticles to be internalized by the endothelial cells and subsequently releasing their cargo within the CNS. Such targeted delivery systems are known to enhance the efficacy of drugs while reducing systemic side effects.

Another approach is the transitory disruption of the BBB to allow for the passage of therapeutic agents. To bring about this short and abrupt disruption, various physical and chemical methods are employed, including the use of hyperosmotic agents (e.g., mannitol) that can induce shrinkage of endothelial cells, thereby increasing permeability. Additionally, other means like focused ultrasound (FUS) combined with microbubbles are used which are known to have significant effect on opening the BBB transiently. When ultrasound is applied, the microbubbles vibrate and induce small openings in the BBB, allowing for the delivery of various therapeutic molecules, including large drugs or genetic material (Kim et al., 2023b). This is a strategy employed even for the precise targeting and controlled release of the intended drug, leading to minimal collateral damage to surrounding healthy tissue.

Leveraging the biological transport mechanisms for the delivery of drugs across the BBB is another promising strategy that involves utilizing endogenous transport systems (like the carrier-mediated transport) that naturally transport substances across the BBB. For instance, glucoproteins like glucose transporters can be exploited to deliver therapeutics that mimic glucose. Similarly, the transport of conjugated therapeutic agents can be enhanced using monoclonal antibodies or antibody fragments that target specific receptors on the BBB. The potential of exosomes and extracellular vesicles as natural vehicle systems are also explored for crossing the BBB as these explicit vesicles can be specifically engineered to carry drugs or RNA therapeutics (Ramos-Zaldívar et al., 2022). They can prove to be quite natural for transport of drugs that are generally utilised by cells to shuttle molecules across the barrier.

Even though the BBB is a highly selective membrane intended to protect the brain from toxins and invading pathogens, despite its semipermeable nature, the BBB is mostly impenetrable to most drugs, especially large or hydrophilic molecules, which restrict their entry into the brain and bloodstream. Nanoparticles have an inherent quality to overcome this challenge through several engineered mechanisms by exploiting the physiological transport pathways and disease-specific BBB alterations (Jiménez et al., 2025).