Metal nanoparticles in neuroinflammation: impact on microglial dynamics and CNS function

Abstract

Microglia, the primary immune cells of the central nervous system (CNS), are crucial in maintaining brain homeostasis and responding to pathological changes. While they play protective roles, their activation can lead to neuroinflammation and the progression of neurodegenerative diseases. Metal nanoparticles (NPs), due to their unique ability to cross the blood–brain barrier (BBB), have emerged as promising agents for drug delivery to the CNS. In this way, we aim to review the dual role of metal-containing NPs, gold (AuNPs), silver (AgNPs), iron oxide (IONPs), zinc oxide (ZnONPs), cobalt (CoNPs), titanium dioxide (TiO₂NPs), and silica (SiO₂NPs) in modulating microglial activity. Some NPs promote anti-inflammatory effects, while others exacerbate neuroinflammation. We examine how these NPs influence microglial activation, focusing on their potential therapeutic benefits and risks. A deeper understanding of NP-microglia interactions is crucial for developing safe and efficient treatments for neuroinflammatory and neurodegenerative disorders.

---

Masood Alaei

Masood Alaei holds a Bachelor's degree in Medical Laboratory Sciences from Qazvin University of Medical Sciences. As a member of the Universal Scientific Education and Research Network (USERN), he has been actively involved in research, authoring review articles on nanotechnology and conducting original laboratory-based research projects.

Khadijeh Koushki

Khadijeh koushki is a researcher in the field of immunology, who works as a PostDoc researcher at The University of Texas Health Science Center at Houston (UTHealth). She has published several articles on topics such as asthma and allergy immunotherapy, drug delivery systems and autoimmune disorders. She has also received a PhD degree in immunology from Mashhad University of Medical Science.

Kimia Taebi

Kimia Taebi earned a Bachelor's degree in Medical Laboratory Sciences from Qazvin University of Medical Sciences. She is a member of the Universal Scientific Education and Research Network (USERN) and has contributed to various scientific publications. Her work includes review articles in the field of nanotechnology as well as original research articles in laboratory sciences.

Mahdieh Yousefi Taba

Mahdieh Yoosefi Taba earned a Master's degree in Anatomical Sciences and Cell Biology from Mashhad University of Medical Sciences. Her research focuses on aging models, with a particular emphasis on investigating the protective effects of therapeutic agents against oxidative stress in infertility and hippocampal dark neurons.

Samaneh Keshavarz Hedayati

Samaneh Keshavarz Hedayati is a researcher in the field of pharmacology and microbiology, who works as a research demonstrator in Qazvin University of Medical Science in Iran. She has also received a MSc. degree in microbiology.

Sanaz Keshavarz Shahbaz

Sanaz Keshavarz Shahbaz is a researcher in the field of immunology, who works as a research assistant professor at Qazvin University of Medical Science in Iran and PostDoc research associates at The Jackson laboratory for genomic medicine, Farmington, CT, USA. She has published several articles on topics such as asthma and allergy immunotherapy, transplantation immunology, cancer, drug delivery systems and autoimmune disorders, neuroimmunology. She has also received a PhD degree in immunology from Mashhad University of Medical Science.

---

1. Introduction

Neuroinflammation is increasingly recognized as a pivotal factor in the pathogenesis of various central nervous system (CNS) disorders, including neurodegenerative diseases such as Alzheimer's and Parkinson's. This inflammatory response, while essential for maintaining homeostasis and responding to injury, can become detrimental when dysregulated, leading to neuronal damage and exacerbation of disease progression. Microglia, the resident immune cells of the CNS, play a dual role in neuroinflammation; they are crucial for both protective responses and the development of inflammatory processes.¹

Recent advancements in nanomedicine have highlighted the potential of polymer and metal nanoparticles (NPs) as innovative therapeutic agents capable of modulating microglial activity and influencing neuroinflammatory responses. Recently, we reviewed polymeric NP carriers applied to deliver microglial inhibition in neurological disorders with remarkable results, showcasing the promising role of these NPs in microglial modulation during drug delivery.²

In addition, due to the unique physicochemical properties—such as high surface area, tunable size, and functional versatility—Metal NPs can effectively cross the blood–brain barrier (BBB),³ presenting new opportunities for targeted drug delivery in treating CNS disorders. Various metal-containing nanoparticles, including gold (AuNPs),⁴ silver (AgNPs), iron oxide (IONPs), zinc oxide (ZnONPs), cobalt (CoNPs), titanium dioxide (TiO₂NPs), and silica (SiO₂NPs), have been shown to interact with microglia, either promoting anti-inflammatory effects or exacerbating neuroinflammation.⁵

In this way, this review aims to provide a comprehensive analysis of metal nanoparticles' impact on microglial dynamics and their implications for CNS function. By examining the complex interplay between these nanomaterials and microglial cells, we seek to elucidate their potential therapeutic benefits and risks in addressing neuroinflammatory conditions. Understanding these interactions is crucial for developing safe and effective treatments for neurodegenerative diseases and advancing the field of nanomedicine.

2. Microglia and their neuroinflammatory roles

Microglia are macrophage-like innate immune cells in the central nervous system (CNS), serving as the brain's primary effector cells that monitor the CNS for infections and injuries.^6–8 As the first responders to foreign pathogens and harmful particles in the brain, microglia act as key indicators of brain damage.^9–11 Constituting 20% of glial cells located in the brain, microglia originate from hematopoietic stem cells.¹² During brain development, these cells enter the brain via circulation and can exhibit neurotoxic or neuroprotective responses in their microenvironment.¹³

Neuroprotective functions of microglia include maintaining homeostasis by regulating the brain's internal environment, metabolic regulation, and facilitating immune responses.^14,15 In their resting state, known as the M0 phenotype, microglia clear apoptotic debris, remove dysfunctional synapses, and support pruning in developing brains. This process involves synaptic remodeling, phagocytosis of cells with intracellular inclusions, neuronal feedback,¹⁶ facilitating myelination,¹⁷ neurogenesis, and trophic maintenance of neurons.^18,19 These functions are crucial for preserving a healthy brain environment.

Microglia also have two activated states: the “M2” anti-inflammatory phenotype and the “M1” proinflammatory phenotype. M2 microglia are responsible for healing-related actions, such as maintaining homeostasis and promoting anti-inflammatory processes. They contribute to the generation of anti-inflammatory cytokines and neurotrophic agents.^10,20,21 In contrast, M1 microglia are the first line of defense, responsible for homeostasis and pro-killing functions. They can produce proinflammatory cytokines interleukin-1b (IL-1b), IL-17, IL-12, IL-6, IL-18, IFN-c, IL-23, inducible nitric oxide synthase (iNOS), tumour necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), reactive oxygen species (ROS), prostaglandin E2 (PGE2), and (MHC-II).^22,23

Although the pro-inflammatory functions of the M1 phenotype are protective in certain situations, excessive release of cytotoxic substances has been attributed to the development of neuroinflammatory disorders.²⁴ Many studies have shown that microglial activation plays a pivotal role in the pathogenesis of neurodegenerative disorders, including Parkinson's disease, Alzheimer's disease (AD), psychiatric disease, ischemic disease, traumatic brain injury, and stroke.^10,25–27 Microglia become activated in response to pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and certain nanostructures, triggering a pro-inflammatory response.

To perform their surveillance functions, microglia are equipped with different signaling immunoreceptors, such as Toll-like receptors (TLR4 and TLR2), complement phagocytic receptors (CR4 and CR3), and scavenger receptors (Cluster of Differentiation-36 (CD36) and CD204) to interact with extracellular species.^25,28,29 When neurons are exposed to harmful stimuli, they begin to generate “help me” signals, including fractalkine, interleukin-34 (IL-34), and CX3C chemokine.^30,31 In response, microglia become activated and release proinflammatory cytokines, including TNF-α and IL-1β, along with neurotoxic molecules, such as ROS.³² Moreover, activated microglia can release glutamate, which causes an increase in the neuronal and neurite number, thereby contributing to neurodegenerative disorder exacerbation.^25,33

Upon stimulation of microglial surface receptors, several signaling pathways become activated. They induce the production of inflammatory cytokines, the NLRP inflammasome activation, and beta-secretase enzyme (BACE) expression,²⁹ ultimately driving neuroinflammation and neuronal death. Microglia can also accidently damage neurons while attempting to limit infections by producing cathepsin B, superoxide, nitric oxide, and derivative oxidants.³⁴ Furthermore, microglia-mediated reduction in insulin-like growth factor 1 (IGF-1) and nutritional brain-derived neurotropic factor (BDNF) contributes to neuronal death^35,36 (Fig. 1). These mechanisms highlight the potential of microglia M1 in the beginning and progression of neurodegenerative diseases.

Fig. 1 Normal functions of microglia in the CNS.

Given the crucial role of microglia, particularly M1 microglia, in neuroinflammatory processes, potent inhibitors that target microglial immune activity may offer promising strategies for addressing these issues.

Resting microglia, known as M0 microglia, perform multiple health-promoting functions. They have the potential to support neuronal progenitors in the neurogenesis process. Additionally, they can appropriately eliminate cell debris and dead cell bodies through phagocytosis. Moreover, M0 microglia can phagocytose unnecessary synaptic connections (called synaptic pruning) to leave more space to form new connections between neurons. An oligodendrocyte is a cell that is responsible for forming myelin around axons. Interestingly, M0 microglia participate in this process by assisting oligodendrocytes. Microglia M0 also contribute to the neuronal feedback mechanism. When neurons are activated, microglia use negative neuronal feedback to prevent neuronal overactivation, thus leading to a balanced neuronal environment. Additionally, resting microglia can play a role in myelin clearance by attempting to phagocytose myelin debris to prevent impaired neurogenesis.

3. Inhibitors of microglial immune activity

According to microglia's vital role in neuroinflammation and the progression of neurodegenerative diseases, inhibiting their activity is a prominent therapeutic solution. Several compounds, including resveratrol, curcumin, cannabidiol,³⁷ ginsenosides, flavonoids, sulforaphane,³⁸ candesartan cilexetil,³⁹ propentofylline, luteolin,⁴⁰ quercetin,⁴¹ and minocycline,⁴² are available as conventional and potent inhibitors of microglial activity. Bellow, some of these compounds and their inhibitory effects on microglia are briefly discussed.

Resveratrol, a polyphenol abundant in peanuts, raisins, red grapes, and berries, possesses anti-inflammatory, antioxidant, and antiapoptotic properties.^43,44 Studies have illustrated that resveratrol can limit microglial activity and mitigate rotenone-induced neurotoxicity, CD11 (a microglial activity marker), TNF- α, and IL-1β.⁴⁵ Curcumin, another well-known inhibitor, is a potent anti-inflammatory and antioxidant agent found in turmeric. Interestingly, curcumin plays a suppressive role in microglial activity and decreases microglia-induced inflammatory cytokines.⁴⁶ It can also block the MAPK signaling pathway, which further inhibits the activation of NF-κβ.⁴⁷ Curcumin suppresses the production of COX-2 and other inflammatory cytokines by modulating TLR4 signaling.⁴⁸ Quercetin, a natural flavonoid present in vegetables and fruits, namely green tea, onions, apples, red grapes, and berries, is also a potent inhibitor of microglial activity due to its antioxidant and anti-inflammatory properties.⁴¹ The treatment with quercetin reduces TLR-4 expression in the hippocampus and cortex, a key receptor involved in microglial activation.⁴⁹ In addition, it can reduce the expression of ionized calcium-binding adapter molecule 1 (Iba-1), IL-1β, TNFα, and COX2.⁵⁰ Minocycline, a well-known antibiotic, has also been extensively studied for its ability to inhibit microglial function, reducing the number of microglial inflammatory mediators.^51,52 Minocycline can also reduce MHC-II expression in microglia.⁴²

While these drugs offer significant potential in mitigating microglial immune responses, drug delivery to the CNS is still a considerable challenge because of the restrictive nature of the blood–brain barrier (BBB). Its specific structure, surrounding cells, and molecular transport mechanisms limit the efficient delivery of many therapeutic agents. Therefore, the following section further discusses these challenges and potential solutions.

4. CNS drug delivery through the BBB and its challenges

BBB, along with extracellular matrix (ECM) and nonfenestrated monolayer of cells, significantly controls the microenvironment of CNS neurons. These structures protect the CNS from circulating toxins, infectious agents, and harmful substances, such as foreign microorganisms.^53–56 The BBB is formed by endothelial cells, whose proliferation is stimulated by neighboring cells such as astrocytes (which surround brain vessels) and pericytes (which help maintain the integrity of the BBB)⁵⁷

Various transport systems control the traffic of substances across the BBB, including fenestra, transendothelial channels, pinocytotic vesicles, active efflux transport proteins, and breast cancer resistance proteins.⁵⁸ These systems are crucial in controlling the flow of specific drugs and essential nutrients into the CNS. Passive distribution via a paracellular or transcellular pathway for low molecular weight or lipophilic substances (the majority of CNS-targeting drugs); vesicular trafficking, such as adsorptive-mediated transcytosis (for positively-charged substances); receptor-mediated transcytosis (an energy-dependent pathway for proteins hormones and proteins); and carrier-mediated transport (for amino acids and glucose) are some examples.^59–61 The BBB's relative impermeability is primarily due to tight junctions between endothelial cells.^62,63 The mentioned mechanisms and complexes are potential obstacles for most drugs to enter the CNS, making drug delivery challenging with high failure rates and increased costs.⁶⁴ Even if drugs manage to cross the BBB, achieving therapeutic concentrations within the CNS can be difficult. Ensuring that drugs are effective without causing adverse side effects and neurotoxicity remains a critical challenge.⁶⁵ Also, CNS disorders often require targeted treatments that are tailored to individual patients. Achieving this specificity in drug delivery systems is complex and ongoing.⁶⁶ Moreover, many conventional therapeutic agents suffer from low bioavailability due to rapid metabolism or elimination, leading to degradation. Therefore, encapsulating drugs can protect them from degradation and improve their pharmacokinetic profiles.⁶⁷ The ability to control drug release is also vital for maintaining therapeutic concentrations over time and avoiding excessive drug dosages, which many conventional drugs lack this ability.⁶⁸ These problems can lead to ineffective treatment for CNS disorders such as cerebral malignancies due to low brain penetration. Over the last decade, researchers have developed various technologies to overcome these challenges. One promising approach is using targeted vectors (peptides, proteins, antibodies, or specific formulations) to aid the transport of drugs across the BBB.⁶⁹ Additionally, nano-delivery systems have gained attention as a novel strategy. These systems offer the possibility to improve therapeutic precision and maintain medicine efficacy while minimizing toxicity.^23,70

5. Nanoparticles for drug delivery to the brain

Advances in biotechnology have shifted therapeutic approaches from conventional medicine to nanotherapeutic agents.⁷¹ Due to the challenges linked to macromolecular drugs crossing the BBB and their inability to target specific sites and ineffective dosages, nanotherapeutics have gained significant attention for drug delivery to the CNS and targeting microglia-related neuroinflammation.⁷² Nanomaterials include nonpolymeric, lipid-based, polymer-based, and metal-based nanoparticles. These NPs range in diameter from 1 to 100 nanometers (nm). These ultrafine particles exhibit unique chemical and physical features that differ significantly from larger particles of the same substance because of their high surface area-to-volume ratio.^73,74 Some NPs exist in the environment, while others are engineered in industrial settings.⁷⁵

Some NPs can traverse vessel walls and enter brain tissue. This ability is mainly attributed to their physiochemical characteristics, including size, shape, surface chemistry, surface charge, and surface traits.⁷⁶ Therefore, engineering the NPs to modify their morphological features enhances their ability to cross the BBB. One strategy involves designing the NPs in combination with elements specific to pathological sites and BBB-penetrating molecules, such as the spontaneous exploitation of NPs with trans-Golgi network (TGN) peptides and the cancer cell-specific aptamer AS1411. Such modification can remarkably improve BBB penetration and target delivery.⁷⁷ The shape and surface characteristics of NPs also influence how microglia internalize them;⁷⁸ for instance, spiky “urchin-shaped” gold NPs(AuNps) show higher levels of microglial uptake in contrast to rod or spherical-shaped AuNPs.^72,79 Hence, the way microglia take NPs up is highly dependent on the design of the NP surface and properties.⁸⁰ Microglia internalize NPs primarily through active processes like invagination and endocytosis.⁶⁹ However, certain NPs may also passively diffuse across the cell membrane. Furthermore, the uptake of NPs varies between microglial phenotypes. Compared with resting microglia, lipopolysaccharide (LPS)-activated microglia display greater dendrimer uptake, which is associated with increased endocytosis.⁸¹

Once NPs reach the brain tissue, they can release their therapeutic cargo at the target location in a time-dependent way and navigate the drugs (genes, small molecular agents, and biomolecules) to the target organelle without being trapped in endo/lysosomes. Various strategies have been developed to facilitate lysosomal escape. One common approach is the proton sponge effect, where pH-sensitive nanoparticles swell and disrupt the lysosomal membrane upon exposure to the acidic environment, leading to the release of their contents into the cytosol. Other methods include osmotic lysis, which results from the disassembly of nanoparticles in response to low pH, and mechanical disruption techniques that utilize nanomechanical actions or photochemical processes to destabilize lysosomal membranes.⁸² This controlled release mechanism decreases the required drug dosage and side effects of using nanomaterials.^56,83,84 Engineering NPs is also critical for drug delivery. One example involves using stimulus-sensitive bonds to ensure the accurate release of cargo in the expected areas in response to spatial variations in redox capacity.⁸⁵ Additionally, NPs designed with epidermal growth factor (EGF) and two types of bioresponsive bonds that enhance vascular permeability⁸⁶ can deliver drugs directly to subcellular organelles, improving drug efficacy in the brain.^87,88 Such designs have been employed to deliver DNA-binding agents and ROS-generating drugs into mitochondria,^76,89 facilitating the treatment of stroke, glioma, epilepsy, and AD. Besides, the unique electrical and optical traits of some nanoparticles enable them to treat CNS disorders.⁷¹

Put simply, NPs favor the treatment of neurodegenerative disorders by delivering essential drugs to the brain, which is partially impossible for macromolecular drugs to reach alone. Nonetheless, metal-containing NPs hold promise for enhancing drug delivery performance compared to NPs alone. However, they also present side effects such as toxicity in the brain by switching M0 microglia to the M1 phenotype. Alternatively, they may alleviate the neuroinflammation by promoting the M2 phenotype. Therefore, the following section further discusses how metal-containing NPs, as multifaceted substances, influence brain health and neuroinflammatory conditions in detail.

6. Metal-containing NPs: a double-edged sword

Inorganic NPs, including metals (such as iron, silver, and gold) and metal oxides (including zinc oxide, iron oxide, titanium dioxide, cerium oxide, etc.), have gained considerable interest in recent years because of their diverse usages across medical, sunscreen, cosmetic, and industrial fields.⁹⁰ These metal-containing NPs possess unique physicochemical features, making them helpful in diagnosing and treating CNS disorders.⁹¹ Their ability to translocate into the CNS through the BBB, eye-to-brain, nerve signaling pathways, and cell uptake opens new possibilities for therapeutic interventions.⁷⁵

Once inside the brain, metal-containing NPs are immediately internalized by microglia and astrocyte-like (ALT) cells. M1 microglia produce CCL2 and proinflammatory cytokines, for instance, NO, IL-12, IL-1β, and IL-6, which result in acute neuroinflammatory reactions. On the contrary, the M2 phenotype releases anti-inflammatory cytokines such as TGF-β, IL-10, and IL-4, aiding the resolution of neuroinflammation and repairing the damaged brain.⁹² Metal-containing NPs can influence this polarization, with some promoting M1 activation and exacerbating inflammation, while others encourage the M2 phenotype, facilitating neuroprotection and recovery.⁹³

Metal NP-induced M1 phenotype can exert neurotoxic effects through various mechanisms, including the generation of ROS, which leads to oxidative stress, inducing neuronal apoptosis and necrosis and contributing to neurodegenerative diseases.⁹⁴ Furthermore, metal NPs can trigger the activation of microglia, leading to the release of pro-inflammatory cytokines, exacerbating neuroinflammation, and compromising neuronal health.⁹⁵ The neurotoxic potential of metal NPs is significantly influenced by their physicochemical properties. Smaller NPs generally exhibit higher reactivity and greater cellular uptake, which can enhance their therapeutic efficacy but also increase the risk of toxicity. Surface modifications, such as PEGylation, can alter NP-cell interactions, improve circulation time, and reduce immunogenicity, potentially mitigating some toxic effects.⁹⁶ The neurotoxicity of metal NPs is often dose-dependent, with low concentrations potentially eliciting beneficial effects by modulating microglial activity and promoting anti-inflammatory responses. Higher concentrations can overwhelm cellular defense mechanisms, leading to toxicity. This highlights the crucial need to optimize dosages in therapeutic applications to maximize efficacy while minimizing adverse effects.⁹⁷ Chronic exposure to metal NPs may lead to cumulative neurotoxic effects that are not immediately apparent. NP prolonged exposure potentially results in significant alterations in microglial function and neuronal integrity, leading to long-term cognitive deficits or the exacerbation of existing neurological conditions.⁹⁸

For instance, silver nanoparticles (AgNPs) are able to promote M1 polarization and induce neurotoxicity. Duffy et al. reported that AgNPs triggered the production of proinflammatory cytokines like TNF-α in BV2 microglial cells, leading to neuroinflammatory responses.⁹⁹ Additionally, AgNPs have been shown to enhance the level of the proinflammatory chemokine CXCL13 in microglia, astrocytes, and Neuro2a (N2a) cells, further elevating the levels of IL-1β.¹⁰⁰ Besides silver, other metal-based NPs, like titanium dioxide nanoparticles (TiO₂NPs), have been linked to neuroinflammatory responses. TiO₂NPs can activate inflammasomes and nuclear factor-κB (NF-κB), activating microglia and subsequent inflammation.⁷⁵

Despite these proinflammatory effects, some metal-containing NPs also exhibit anti-inflammatory properties. AuNPs, for instance, have been evidenced to prevent the proinflammatory reactions in microglia by promoting M2 phenotype, thereby contributing to CNS repair.¹⁰¹ Similarly, exposure to AgNPs has been found in another article to be associated with a reduction in inflammation. This could be possibly due to the detoxification of silver ions through sulfidation and the activation of hydrogen sulfide-synthesizing enzymes.¹⁰² Moreover, iron oxide nanoparticles (IONPs) have been demonstrated to inhibit the production of IL-1β in LPS-stimulated microglia, further underscoring the potential neuroprotective role of metal-based NPs.¹⁰³ (Fig. 2).

Fig. 2 The possible functions of metal-containing nanoparticles in microglial activation.

Although remarkable endeavors have been made to understand the neurotoxic and neuroprotective effects of metal-containing NPs, much remains to be learned about their role in neuroinflammation. Additionally, since studies have shown that microglia activation can serve as an early warning and defensive response against exogenous NPs that invade and accumulate in the CNS, it is crucial to investigate the interaction between various metal-containing NPs conjugated with specific drugs and microglia. Hence, additional exploration is needed to fully exploit the ability of nanotechnology to treat CNS disorders.

In the following section, we aim to comprehensively discuss some well-known metal-containing NPs and their conjugation with certain drugs, highlighting how NP uptake by microglia influences treatment outcomes (Table 1).

Table 1 The outcomes of using metal-containing NPs in other studies^a

NP type	The surface coating	NP properties	Cell type/animal models	Mechanisms & outcomes	Ref
a Abbreviations: Au, gold; Ag, silver; IO, iron oxide; Co, cobalt; ZnO, zinc oxide; TiO2, titanium dioxide; SiO2, silica; Si, silicon.
Au	Gold-quercetin NPs	27 nm, 100, 200, 400 μg mL^−1	LPS-stimulated microglia	Significant decrease in both the transcriptional and translational levels of inducible NO synthase, cyclooxygenase-2; COX-2 and iNOS	110
				Inhibiting the release of NO and proinflammatory PGE2 from LPS-stimulated microglia without causing any cytotoxic effect
Au	AuNP-FIB-BS hard corona	50–3 nm, dose: 26 μg mL^−1	Murine BV2 microglia	Significant decrease in oxidative stress and ROS generation	111
				Significant increase in cellular uptake
Au	Ephedra sinica Stapf extract extract-capped AuNPs	57.6 ± 3.07 nm	Microglia	Decrease in the production of the proinflammatory cytokines, including IL-1β, IL-6, and TNF-α in LPS-stimulated microglia through the downregulation of JAK/STAT, NF-κB, IKK-α/β, JNK, and p38 MAPK signaling pathways	112
				Upregulation of NQO1 and HO-1
				Activation of AMPK and Nrf2
Au	Polyethyleneglycol-coupled GNPs	8.09 ± 3.60 nm (85 × 10^6 nL^−1)	Microglia	Self-limited, transient, and predominantly localized cellular response of microglia at the injection site within 3 to 90 days following intracerebral injection	113
				No chronic microglial response by NPs
Au	Paeonia moutan-functionalized GNPs	100 nm, 5, 10 and 20 μg mL^−1	BV2 microglia and C57BL/6 mice/mouse model of parkinsonian	Inhibiting the inflammatory cytokines (IL-1β, IL-6, and TNFα) and NO synthesis	115
				Trapping the reactive oxygen in LPS-stimulated BV2 murine microglia suffering from PD
				Significant reduction in the expression of inflammatory COX2 and iNOS
				Increase in the expression of tyrosine hydroxylase
				Improving motor coordination and alleviating the neuroinflammation in the Parkinson model
Au	Paeonia moutan-functionalized GNPs	190–450 nm	BV2 microglia	Decrease in formation of intracellular α-syn oligomers, pro-inflammatory cytokines (IL-6 and TNF-α) secretion, and α-syn internalization, in vitro	116
				Lowered α-syn-induced production of ROS and NO in microglia
				Nuclear translocation of NF-κB
				Suppression the expression of Iba-1 by α-syn-challenged microglia
Au	Anthocyanin-loaded poly (ethylene glycol)-AuNPs	135 ± 5 nm	Aβ1-42-induced mouse model and BV2 microglia	Reduction in Aβ1-42-induced neuroapoptotic markers and neuroinflammation by restricting the p-GSK3β/NF-κB/p-JNK pathways in both in vivo and in vitro AD models	118
				Significant mitigation in Aβ-induced apoptosis in both BV2 microglia and the mouse hippocampus by reducing Cyt. c release, Bax protein expression, and increasing Bcl2 protein levels
				Reduction in the production of Iba-1 and GFAP in microglia
				Mitigating the expression of iNOS and p-NF-κB proteins
Ag	AgNPs	20 nm, 50 μg mL^−1	Mouse BV-2 microglia	Decrease in microglial growth by AgNPs and CdTe-QDs by stopping the cells in the G1 phase (CdTe-QDs) or S phase (AgNPs and CeO2NPs) of the cell cycle	129
Ce	Cerium oxide NPs	25 nm, 100 μg mL^−1		Significant reduction in Aβ uptake by BV-2 microglia with AgNPs and CeO2NPs, but not CdTe-QDs
	Cadmium telluride quantum dots	3.8 nm, 3 or 10 μg mL^−1		No impacts on the secretion of IL-6, IL-1b, and IFNg by Aβ, nor NPs or their combinations
				Significant increase in TNFa secretion by CeO2NPs
Ag	—	20 nm, dose: 50 μg mL^−1	Mouse BV-2 microglia	Efficiently blocking the Aβ uptake by microglia	130
Ag	—	20 nm	Mouse BV-2 microglia	Impairing Aβ clearance by BV-2 microglia by competing with Aβ for scavenger receptors	131
Ag	—	10 nm, 6, 3, and 1 μg mL^−1	BV2 microglia	Releasing soluble factors like NO and H2O2 from glial cells	121
				Significantly inhibiting the induced ROS and cytokines (TNF-α, MCP-1, and IL-6) from LPS-activated BV-2
				Decreasing cell viability of BV-2 by releasing H2O2 from ALT cells through indirect AgNP exposure
Ag	—	23 nm diameter	Glial cells	Destruction of the cerebellum granular layer, causing cerebellar ataxia-like symptoms in rats	124
Ag	—	23.44 ± 4.92 nm, 5 μg mL^−1	BV2 microglia cell lines of mouse	AgNPs-induced M1 polarization of microglia in a time- and dose-dependent way by inhibiting the fusion of autophagosomes with lysosomes	126
				Increasing the expression of pro-inflammatory genes such as IL-1β, TNF-α, Iba-1, NF-κB, and MCP-1 in BV2 cells
				Reducing the mRNA expression of anti-inflammatory cytokines
Ag	—	3–5 nm, dose: 5–12.5 μg mL^−1	Murine BV-2 microglia	Inducing pro-inflammatory cytokine secretion such as IL-1β secretion and gene expression of CXCL13, GSS, and macrophage MARCO	100
				Altering protein and gene expressions of Aβ deposition by inducing the expression of amyloid precursor protein (APP) gene
Ag	—	49.7 ± 10.5 nm	Microglia	Reducing LPS-stimulated NO, TNF-α, and ROS production	133
				Significant anti-inflammatory effects
				Reducing microglial toxicity to dopaminergic neurons
Ag	—		Human microglia cells (HMC3)	M1 to M2 phenotype switch	134
				Enhancing the expressions of anti-inflammatory markers including transforming TGF-β and IL-10
				A significant reduction in mRNA expressions of TNF-α and IL-6
				Biogenic AgNPs were protected against oxidative stress and neuroinflammation by targeting Nrf2/HO-1 and TLR4/MyD88 signaling pathways
Ag	—	18 ± 1.8 nm	Microglia	Neurobehavioral alterations in offspring	172
				Body fat increase
				Long-term gut dysbiosis
				Reducing the microglial counts
IO	—	∼65 nm	Cultured rat microglia	Time- and concentration-dependent uptake	136
				Longer incubation periods of exposure or higher concentrations or severely attenuated cell viability
IO	—	58.7 nm, 1–510 μ Fe/mL	Primary murine microglia	Attenuation of the IL-1β production, but not TNF-α, mediated by their accumulation in lysosomes and affecting the secretory lysosomal pathway of cytokine recessing	137
				Suppression of IL-1β converting enzyme in IONP-treated murine microglia by decreasing the activity of cathepsin B
Magnetic iron oxide (γ-Fe2O3)	—	11 ± 3.5 nm	rTg4510 tau-mutant mice	A significant decrease in the number of activated microglia in comparison with the same concentration of the free peptides by stabilizing the peptide to the γ-Fe2O3 NPs	138
Fe2O3	—	γ -Fe2O3: (31 ± 17) nm	BV2 microglia	Proliferation of microglia	139
		α-Fe2O3NP: (22 ± 5) nm		Increased phagocytosis
		Dose: 0.02, 0.2, 2 mol Fe/L of Fe2O3-NP suspensions or FeCl3 solution		Higher release of ROS and NO by microglia
Co	—	50 nm	C57BL/6J mice brain	Toxic effects and inflammatory responses in BV2 microglia and mice by activating the NOX2 (NADPH oxidase 2)	142
		Dose: 1.25, 2.5 and 5 μg mL^−1	BV2 microglia	Catalyzing ROS production, IL-1β, NLRP3, accompanied by tau phosphorylation
Co	—	96 and 123 nm	Microglia	Microglial activation	143
ZnO	—	38.52 ± 2.82 nm, dose: 6.6 μg mL^−1	Mouse microglia N9 cell line	Disrupting the MMP activity and subsequently inducing the apoptotic pathway in the microglia by NADPH oxidase-independent ROS and ATP depletion	146
				Disrupting mitochondrial membrane potential
				Microglia apoptosis, involving altered intracellular calcium (Ca^2+) level, mitochondrial ROS production, caspase-9 and -3 activation, ERK and p38 phosphorylation, and cytochrome-c release
ZnO	—	50 nm, dose: 10 μg mL^−1	Murine BV-2 microglia	Increase in the ROS levels and oxidative stress in BV-2 cells in a time-dependent manner through autophagy and PINK1/parkin-mediated mitophagy	150
				Increasing count of swollen mitochondria and autophagosomes
ZnO	—	20 nm (5, 10, 20, 40, and 80 μg mL^−1)	Murine BV-2 microglia	Influencing the lysosomal destabilization	151
				Inducing extensive cellular and organelle (mitochondria, lysosome), ROS accumulation, and consequently nonapoptotic cell death, leading to the release of lysosomal enzymes
				Promoting inflammation by cell debris and accumulating ROS at the CNS level
ZnO	—	42.31 ± 17.94 nm, dose: 30 μg mL^−1	BV2 microglia cell line	Driving microglia and inflammatory responses in the CNS by activating the Ca^2+-dependent ERK, p38, NF-κB pathways	152
ZnO	—	26.4 ± 2.3 nm, 5 μg mL^−1	BV2 microglia	Microglial activation and proliferation by ERK and Akt signaling pathways	153
ZnO	—	50 nm	Microglia	Induction of tau protein expression, microglia activation, and oxidative stress in the brain, resulting in neurotoxicity	154
ZnO	Luteolin/ZnO NPs	17 nm	Microglia	Regulating microglia polarization by targeting C/EBPA and alleviating inflammatory injury by modulating the redox-sensitive signal transduction pathways	155
TiO2	TiO2 NPs (Degussa P25)	330 nm, dose: 2.5–120 ppm	BV2 microglia	Upregulation of NF-κB and ERK/MAPK	148
				Stimulating BV2 microglia to have an prolonged and immediate release of ROS
				Damaging neurons at low concentrations in cultures of the brain striatum, probably by microglial-generated ROS
				Influencing genomic pathways linked to cell cycling, upregulation of apoptotic pathways, inflammation, mitochondrial bioenergetics, and downregulation of energy metabolism
TiO2	—	20–30 nm, 0.1 to 200 μg mL^−1	BV2 microglia	TiO2NP accumulation in BV-2 cells	157
				Induction of oxidative stress and mitochondrial dysfunctions
				Damaging the permeability of cell membranes, inhibiting cell adhesion with a loss of mitochondrial transmembrane potential. Induction of ROS overproduction and reducing cell viability
TiO2	—	1–100 nm	Microglia	Producing excessive ROS via the oxidative burst	158
				Interfering with mitochondrial energy production in vitro
				Damaging membrane integrity
TiO2	TiO2 NPs (Degussa P25)	30 nm	BV2 microglia	Formation of free radicals in cellular and morphological expressions	159
TiO2	—	21 nm, 25–200 μg mL^−1	Male C57BL/6 mice and murine BV2 microglia cell line	Stimulating inflammatory mediators in the brain and neurons in vitro	160
				Significantly elevating pro-inflammatory cytokine (TNF-α and IL-1β) mRNAs and IL-1β protein levels in the brains of LPS-exposed mice
				Enhancing TNF-α production and NF-κB binding activity by LPS-stimulated BV2 microglia
				Causing neuroinflammatory responses by enhancing microglial activation in the preinflamed brain and leading microglia N9 to apoptosis
TiO2	TiO2NPs	20–60 nm/0.25 mg mL^−1 and 0.5 mg mL^−1	Primary microglia	Inducing a significant expression of iNOS and subsequent NO secretion	162
	HAP-NPs			Upregulating the expression levels of MIP-1 and MCP-1 from NP-stimulated microglia by inducing NF-κB activation
				Increasing the production of TNF-α, IL-6, and IL-1β by TiO2-NPs and HAP-NPs
TiO2	—	35 nm, dose: 4–125 μg mL^−1	Microglia N9	Inducing TiO2-induced apoptosis	173
TiO2	—	6 nm, dose: 100–5 μg mL^−1	BV-2 microglia	Inducing IL-1β production and ROS production	174
				Clathrin-dependent endocytosis, phagocytosis, and a slow translocation to the lysosome in BV2 cells
				More TiO2NP uptake in LPS-activated BV-2 than normal BV-2, resulting in more released ROS, IL-6, IL-1β, and MCP-1 levels
SiO2	Fluorescein isothiocyanate -tagged SiO2 NPs	115 nm	Male C57BL/6N mice & microglia	Increasing Iba-1 antibody in the hippocampus	166
SiO2	Silica-coated magnetic NPs containing rhodamine B isothiocyanate dye	50 nm	Murine BV2 microglia	Increasing the expression of Iba1	169
				Increasing the serine protein, especially excitotoxic D-serine secretion in the growth medium of activated microglia from primary rat microglia
				Activation of primary microglia
				Accumulation of ubiquitinated proteins and increasing the inclusion bodies in primary cortical and dopaminergic neurons, cocultured with activated primary microglia
				Reduction of intracellular ATP levels and proteasome activity in cocultured neuronal cells, especially in primary cortical neurons, by D-serine secretion
Si	—	48.53 ± 3.12 nm	Murine BV2 microglia	Significantly increasing caspase-1, ASC, and NLRP3 after stimulation by LPS and SiNPs	170
				Raising the production of inflammatory factors, including IL-6, IL-1β, and TNF-α
				Decreasing the cell viability by increasing the concentration of NP
				Changing the ultrastructure
				Invading the cytoplasm
				Activating the NLRP3 inflammasome
				Releasing a large number of inflammatory factors
				Disrupting cellular antioxidant function
				Inducing ferroptosis
				Increasing intracellular ferrous ion levels
SiO2	—	—	Microglia	Elevating oxidative stress levels
				Activation of microglial functions
Si	—	150–200 nm	Primary rat microglia	Significantly increasing intracellular RNS and ROS productions	149
				Decreasing TNF-α gene expression
				Increasing the expression of COX-2 gene
				Inducing a small but detectable IL-1β release

---

Metal-containing nanoparticles have serious impacts on microglia in the CNS. They can directly influence resting microglia (M0) to switch them to the M1 or M2 phenotype. They can also induce this effect on the M1 and M2 phenotypes, resulting in a phenotypic switch between M2 and M1. In case of a switch to the M1 phenotype, proinflammatory and inflammatory cytokines are likely to be released, resulting in an inflammatory state in the CNS and, consequently, neuronal death. On the other hand, if a phenotype switch occurs to the M2 phenotype, it is probable that anti-inflammatory cytokines will be released, leading to a protective state in the CNS and healthy neurons.

6.1. Gold nanoparticles (AuNPs)

AuNPs possess distinctive physicochemical characteristics, including surface plasmon resonance and high biocompatibility, making them notably attractive for several biomedical uses, such as photothermal and photodynamic therapies. These properties enable targeted heating of tissues and enhanced imaging capabilities, making them versatile tools for both treatment and diagnosis of CNS disorders.^104,105 Gold nanoparticles possess inherent antibacterial properties that make them effective against a range of pathogens, including antibiotic-resistant strains.¹⁰⁶ Their ability to amplify signals also makes them valuable tools in clinical settings as potent biosensors.^107,108 They have been explored in fields like pharmacology, drug delivery, cancer therapy, biosensing, and bio-imaging because of their suitable shape and size.¹⁰⁹ This section summarizes the results of some studies on the effects of these NPs on microglia-mediated neuroinflammation during drug delivery to CNS.

Several researchers have confirmed the anti-inflammatory function of AuNPs in the CNS by influencing microglia. For example, Ozdal et al. revealed that gold-quercetin NPs exhibited superior anti-inflammatory and therapeutic effects compared to free quercetin. These NPs notably reduced the translational and transcriptional levels of inflammation-associated enzymes, PGE2, and nitric oxide (NO) in LPS-stimulated microglia without causing cytotoxic effects. This highlights the potential of AuNPs as carriers to address solubility issues of therapeutic compounds like quercetin.¹¹⁰ Another example involves dihydrolipoic acid (DHLA)-functionalized AuNPs, which act as neuroprotective antioxidants. These GNPs polarize microglia to M2-like phenotype, effectively reducing oxidative stress and NF-κB signaling. Additionally, they support microglial survival by preventing apoptosis.¹⁰¹ Moreover, Kuschnerus and colleagues reported that AuNPs coated with a hard corona composed of fibrinogen (FIB) and bovine serum (BS), in vitro, significantly enhanced cellular uptake and lowered oxidative stress and ROS production in microglia more effectively than AuNPs-FIB, protein corona (PC), and BS-T120W3-AuNPs each alone. This selective formation of AuNP-corona complexes may offer a promising strategy for controlling oxidative stress and improving cellular uptake.¹¹¹ Additionally, in an in vitro study, E. sinica Stapf extract (ES)-functionalized AuNPs lowered proinflammatory cytokine levels by downregulating the NF-κB and Janus kinase/signal transducers and activators of transcription (JAK/STAT) in LPS-stimulated microglia, thereby suggesting that ES-functionalized AuNPs may mitigate neuroinflammation and neurodegenerative disorders.¹¹² Also, Diaz and colleagues¹¹³ evaluated microglial responses to intracerebrally injected PEGylated AuNPs (polyethylene glycol-coupled AuNPs). The results indicated a transient and predominantly localized cellular response of microglia and astrocytes at the injection site with minimal harmful effects on the brain for 3 to 90 days. It was suggested that neural tissues could tolerate PEGylated GNPs well. Interestingly, Hutter et al. discovered that AuNP exposure caused a limited and transient upregulation of TLR-2 and inflammatory markers like IL-1α, NO, and GM-CSF in microglia. Notably, microglial activation occurred in a limited number at a slow pace, highlighting their ability for long-term drug delivery to the CNS.¹¹⁴

AuNPs have also shown privileges in treating neurodegenerative diseases like Parkinson's disease (PD). In this regard, a study utilizing Paeonia moutan-functionalized AuNPs (PM-AuNPs) in a PD mouse model showed that these NPs significantly inhibited the production of NO and inflammatory cytokines and scavenged ROS in LPS-stimulated BV2 microglia all without causing cytotoxic effects. PM-AuNPs reduced levels of COX2 and iNOS, key markers of inflammation, while improving motor coordination in the PD model.¹¹⁵ Consistently, Zhao et al. observed that PM-AuNPs reduced α-synuclein internalization and oligomer formation, as well as decreasing TNF-α and IL-6 levels in vitro. This supports PM-AuNPs’ role in managing PD-related neuroinflammation.¹¹⁶ Additionally, AuNPs have been used to treat Alzheimer's disease (AD). As a study has shown, anthocyanins-loaded GNPs successfully crossed the BBB. They inhibited a key inflammatory pathway in microglia-induced neuroinflammation, p-GSK3β, without harming neurons. GSK-3β mainly regulates the balance between proinflammatory and anti-inflammatory agents in microglia. Intriguingly, it activates the JNK and NF-κB pathways, resulting in enhanced chemokine and cytokine production¹¹⁷ by microglia in AD models. Therefore, anthocyanins-loaded GNPs could also indirectly inhibit NF-κB and JNK pathways. Anthocyanins conjugated with PEG-GNPs (AnPEG-GNPs) could also reduce the expression of Aβ1–42-escalated neuroapoptotic markers in BV2 microglia in mouse AD models, making it a promising therapeutic approach.¹¹⁸

Overall, AuNPs offer considerable advantages, including their anti-inflammatory properties and ability to cross the BBB, making them promising carriers for drug delivery in neurological disorders like AD and PD, with minimal microglia-mediated side effects for neurons and the brain. Nonetheless, more investigation is necessary to address the potential for even mild and transient neuroinflammatory responses associated with AuNPs, ensuring their safety and efficacy in CNS treatments.

6.2. Silver nanoparticles (AgNPs)

Silver nanoparticles (Ag nanoparticles) have been studied for their capability of crossing the BBB and are valuable for addressing challenges linked to the delivery of therapeutic agents to the CNS.¹¹⁹ Microglia mainly take up these NPs,^120,121 suggesting that AgNPs can polarize these cells toward either M1 or M2 phenotypes.¹²² This section discusses various studies exploring the effects of AgNPs on microglia during drug delivery to the CNS.

Several studies have shown that AgNPs can induce neurotoxic effects through microglial activation. For instance, one study evidenced that prenatal AgNP exposure led to cognitive dysfunctions and abnormal behaviors in adults, which were linked to microglial activation.¹²³ Another survey by Hsiao et al. found the toxic effects of AgNPs on neurons were indirectly mediated by the release of NO and H₂O₂ from glial cells. Although, cytokines, namely IL-6 and TNF-α, were not involved in this process.¹²¹ Additionally, in an animal study, intranasal administration of 23 nm AgNPs resulted in microglial activation, destructing the cerebellum granular layer. This process caused cerebellar ataxia-like symptoms in rats, as well as motor dysfunction and impaired locomotor activity.¹²⁴ Autophagy significantly affects microglial inflammation and phenotype transformation.¹²⁵ Shang et al.¹²⁶ explained that AgNPs promoted M1 polarization and inflammation in microglia in a time- and dose-dependent manner by avoiding the fusion of autophagosomes with lysosomes, thereby altering the lysosomal function and impairing autophagy. This finding provides insights into the molecular mechanisms behind AgNP-induced neurotoxicity.¹²⁷ Moreover, Huang et al. reported that AgNPs promoted neuroinflammation, oxidative stress, and Aβ deposition in microglia, which was mediated by the secretion of IL-1β, the production of CXCL13 (C-X-C motif chemokine 13), macrophage receptor with collagenous structure (MARCO), and glutathione synthetase (GSS).¹⁰⁰ One of the key concerns about AgNPs is their potential to exacerbate neurodegenerative diseases like AD. Aβ deposits cause toxicity to neurons as they cause proinflammatory responses and oxidative stress in the CNS.¹²⁸ Since AgNPs and Aβ both are taken up by microglia via the scavenger receptor 1 (Scara1), AgNPs may compete with Aβ for uptake, potentially impairing Aβ clearance and worsening AD pathology.^129–131 Sikorska et al. also observed that the AgNPs accompanied by cerium oxide nanoparticles (CeO₂NPs) reduced microglial phagocytic activity and amyloid-β (Aβ) uptake by BV-2 microglia, which may assist in the AD pathogenesis. AgNPs also attenuated the microglial viability once combined with cadmium telluride quantum dots (CdTe-QDs), favoring the pathogenesis of AD.¹²⁹

On the contrary, some studies suggest that AgNPs can exhibit anti-inflammatory and neuroprotective properties. For example, AgNPs, in combination with CdTe-QDs or CeO₂NPs, even at relatively nontoxic concentrations, could decrease microglial growth by arresting the cell cycle at the G1 phase or S phase, respectively. This suggests a new approach to alleviate neuroinflammation and further disorders.¹²⁹ Likewise, Lyu et al. confirmed that using AgNPs reduced the number of microglia, supporting their anti-inflammatory role.¹³² Moreover, citrate-capped AgNPs have demonstrated both anti-inflammatory and antioxidant effects in microglia. These AgNPs were specifically absorbed by microglia and further reduced LPS-stimulated NO, ROS, and TNFα production, leading to less neurotoxicity of microglia for dopaminergic neurons. Also, LDH release, following AgNP treatment, showed a significant reduction, underscoring the role of AgNPs in heightening neuronal cell viability (Fig. 3).¹³³ Furthermore, the inhibitory role of biogenic AgNPs in LPS-induced neuro-inflammation by HMC3 microglial cells was studied. Cotreatment with AgNPs significantly decreased the production of inflammatory markers while increasing anti-inflammatory markers, facilitating a shift from M1 to M2 phenotype in microglia. Therefore, biogenic AgNPs are able to defend CNS against oxidative stress and neuroinflammation.¹³⁴

Fig. 3 Anti-inflammatory effects of AgNPs on microglial cells (a and b) N9 microglial cells were treated with LPS (500 ng mL⁻¹) with or without AgNPs for a 1 h pulse period. Then, a 24 h chase period was considered. Microglial inflammation was assessed through evaluation of (a) ROS production and (b) TNFα release following AgNP treatment. (c) N9 microglia were treated for 1 h (pulse) with AgNP (50 μg mL⁻¹) and/or LPS (500 ng mL⁻¹). Then, a 24 hours chase period was considered with only LPS present. The medium was then transferred to N27 neurons and incubated for 48 hours. Afterward, the cell viability was assessed through LDH release examination. Adapted from Gonzalez-Carter et al.¹³³

Consequently, the effects of AgNPs on microglia in the context of neurodegenerative diseases remain controversial. While some studies highlight the proinflammatory and neurotoxic potential of AgNPs, others demonstrate their anti-inflammatory and neuroprotective effects. Therefore, AgNPs act as a double-edged sword in neuroinflammation. Further investigation is required to better perceive their mechanisms and ensure their safe and appropriate use to treat CNS disorders.

6.3. Iron oxide nanoparticles (IONPs)

IONPs are a class of magnetic NPs that have garnered considerable interest for their potential applications in biomedicine and bioengineering. IONPs have recently been explored for drug delivery systems, particularly for their ability to modulate microglia activity and reduce neuroinflammation.¹³⁵ Along with it, this section reviews several studies to determine the effect of this NP on microglia-mediated neuroinflammation during drug delivery.

Iron oxide-based metal NPs are primarily internalized by microglia, mainly through clathrin-mediated endocytosis and macropinocytosis, after which they accumulate in the lysosomal compartment.¹³⁶ This accumulation in lysosomes plays a crucial role in modulating microglial activity. Interestingly, Wu et al. showed that accumulated IONP attenuated the expression of IL-1β in LPS-stimulated microglia by affecting the secretory lysosomal pathway. In addition, the IL-1β converting enzyme (ICE) was inhibited in microglia following the treatment with IONP by preventing the activity of cathepsin B, an enzyme responsible for IL-1β activation. These findings suggest that IONPs efficiently suppress IL-1β production, highlighting their potential for use in drug-delivery systems that target inflammation.¹³⁷ Another critical area of investigation is the ability of microglia to alleviate tau pathology in neurodegenerative conditions such as AD. In this regard, Glat et al.¹³⁸ showed the efficacy of iron oxide (γ-Fe₂O₃) NPs in delivering fibrin γ377–395 peptides to nervous tissue. Stabilizing the peptide to γ-Fe₂O₃ NPs significantly decreased the activated microglia in comparison with the same concentration of the free peptides. Therefore, the authors suggested γ-Fe₂O₃ NPs as suitable carriers for the controlled release of medicine in the CNS. Wang et al.¹³⁹ also observed that Fe₂O₃ NPs induced the proliferation of microglia, enhanced phagocytosis, and increased ROS and NO production in microglia. However, the study noted no significant production of inflammatory cytokines, namely, IL-6, IL-1β, and TNF-α, implying that IONPs may boost some microglial functions without causing overt inflammation.

Despite their promising applications, many studies have evidenced the potential detrimental impacts of IONPs on microglia. As reported by Petters et al.,¹⁴⁰ IONP exposure triggered ROS production by microglia, causing cellular and tissue damage. Additionally, the IONP accumulation in microglia could lead to changes in microglial morphology and function, potentially disrupting their usual tasks in the brain. Similarly, Luther et al. noted that prolonged exposure to IONPs compromised microglial cell viability, raising concerns about long-term use of these NPs in the brain.¹³⁶

IONPs offer a noteworthy ability to deliver drugs, particularly in their ability to regulate microglial activity and mitigate neuroinflammation. However, the dual nature of their effects—both as modulators of inflammation and potential toxicity sources—necessitates further investigation. While some studies have shown their efficacy in reducing proinflammatory cytokine production and promoting drug delivery to the CNS, others have indicated possible adverse outcomes, such as the generation of ROS and compromised microglial viability. Consequently, more comprehensive research is required to make sure IONPs are safe and efficient as therapeutic agents for CNS-related conditions.

6.4. Cobalt nanoparticles (CoNPs)

CoNPs have been extensively utilized due to their catalytic, electrical, and magnetic properties. Intriguingly, it has been reported that CoNPs can enter the CNS, possibly due to their resemblance to local air pollutants, which can be inhaled.¹⁴¹ Prolonged exposure to cobalt dust in occupational settings has been associated with cognitive impairments, including reduced memory deficits and attention, showing that cobalt over-intake may contribute to neurodegenerative changes.¹⁴² However, the exact effects of CoNPs on triggering neurodegeneration and the underlying mechanisms remain mostly unexplored.

Recent studies have paved the way for understanding the potential neurotoxic and pro-inflammatory effects of CoNPs. In this way, Li et al. illustrated that CoNPs induced toxicity and inflammatory responses in microglial BV2 cells by activating NADPH oxidase 2 (NOX2). CoNPs in both BV2 cells and mouse brains (the hippocampus and cortex) further catalyzed ROS production and upregulation of IL-1β and NLRP3, which are inflammation-related proteins. Additionally, CoNP exposure was linked to increased tau phosphorylation, which is a hallmark of neurodegenerative diseases.¹⁴² Similarly, a survey by Zheng et al. reported that CoNPs were capable of inducing microglial activation, leading to the expression of oxidative stress-related substances NRF2, heme oxygenase-1 (HO-1), and malondialdehyde (MDA) in the hippocampus and cortex of the rat brain.¹⁴³ These results indicate that CoNPs can induce significant inflammation and oxidative stress in the brain.

While these studies provide initial insights into the impacts of CoNPs, the limited research on this topic underscores the need for further investigations. The potential proinflammatory effects of CoNPs during drug delivery warrant a deeper understanding of their interactions with microglia and their long-term implications for neurodegenerative processes. Continued research is essential to elucidate how CoNPs may contribute to neuroinflammation and cognitive decline, ultimately identifying their safe application in biomedical contexts.

6.5. Zinc oxide nanoparticles (ZnONPs)

ZnONPs can be easily found in various forms. Some physicochemical properties of ZnONPs, including their surface charge, morphology, concentration, purity, and size impact the interaction of ZnO with microglia. ZnONPs have been found to cause neurotoxicity through microglial activation, which is a significant cause of concern.^144,145

Several studies have shown that ZnONPs trigger apoptosis in the murine microglial cell line N9 by generating ROS and depleting cellular energy,^146,147 leading to neuronal damage¹⁴⁸ or self-destructive processes.¹⁴⁹ Wei et al. indicated that ZnONPs significantly raised ROS levels and oxidative stress in a time-dependent way in BV-2 cells, which occurred through autophagy and PINK1/parkin-mediated mitophagy.¹⁵⁰ Moreover, Sharma et al. found that ZnONPs disrupted matrix metalloproteinases (MMPs) and subsequently activated the apoptotic pathway in microglia via NADPH oxidase-independent ROS generation and ATP depletion. This microglial apoptosis exacerbates the existing neuroinflammation.¹⁴⁶ Also, it has been reported that ZnONPs induce a nonapoptotic mode of cell death in microglia, which is probably driven by ROS accumulation, leading to lysosomal destabilization and extensive damage to mitochondria and lysosomes. This nonapoptotic cell death can severely damage the brain by accumulating ROS and releasing lysosomal enzymes and cell debris, resulting in severe neuroinflammation.¹⁵¹ ZnONPs have also triggered several inflammatory responses. For instance, a study claimed that ZnONPs activate NF-κB, Ca²⁺-dependent extracellular signal-regulated kinase (ERK), and p38 pathways in BV2 microglia following tongue instillation.¹⁵² Similarly, Liu et al. revealed that even nontoxic concentrations of ZnONPs led to BV2 proliferation and activation through the Akt (protein kinase B) and ERK signaling pathways.¹⁵³ Another paper studied the acute outcomes of pulmonary exposure to ZnONPs in a rat model. The results indicated that acute exposure to ZnONPs induces microglial activation, tau protein expression, and oxidative stress in the brain, contributing to neurotoxicity.¹⁵⁴

Despite the concerns associated with ZnONPs, some studies have reported potential benefits. In this respect, a survey by Moustafa et al. on diabetic patients revealed that luteolin/ZnONPs could regulate microglial polarization by targeting brain CCAAT/enhancer-binding protein (C/EBPA mRNA). These NPs also alleviated inflammation by modulating redox-sensitive signal transduction pathways. Therefore, it was concluded that luteolin/ZnONPs may offer a novel approach to protecting BBB and preventing neurological complications.¹⁵⁵

The adverse effects of ZnONPs on microglial neuroinflammation appear to outweigh their potential benefits in promoting brain health. Urgent and comprehensive studies should be conducted to thoroughly investigate the possible positive and negative effects of ZnONPs on microglia-related neuroinflammation. This is crucial to determine a safer dosage with minimal side effects for patients suffering from neurodegenerative disorders.

6.6. Titanium dioxide nanoparticles (TiO₂NPs)

TiO₂NPs are widely applied across various sectors, including chemical, electrical, electronic, medical, cosmeceutical, and industrial fields. TiO₂NPs can enter the brain directly through the olfactory bulb and accumulate in the hippocampus. Recent studies have raised concerns about the potential harm TiO₂NPs pose to biological systems, particularly regarding their toxicity to the CNS.¹⁵⁶ Nonetheless, the toxicity of TiO₂NPs to the CNS has been poorly investigated so far.

Rihane et al. evidenced that TiO₂NPs predominantly accumulate in BV-2 cells, promoting mitochondrial dysfunction following oxidative stress. These NPs also cause various side effects, such as damaging the permeability of cell membranes, ROS overproduction, and inhibiting cell adhesion with a loss of mitochondrial transmembrane potential, thereby leading to microglia apoptosis.¹⁵⁷ Additionally, Sheng et al. highlighted that TiO₂NPs contribute to the apoptosis of primary hippocampal neurons and microglia.¹⁵⁸ On top of that, recent reports have indicated that low concentrations of TiO₂ stimulate BV2 microglia to undergo immediate and prolonged release of ROS, damaging neurons in brain striatum cultures.^148,159 Shin et al.¹⁶⁰ reported that ultrafine TiO₂NPs stimulate the release of inflammatory mediators, encompassing IL-1β, TNF-α, and mRNA in the brains of LPS-exposed mice. These NPs also enhanced NF-κB binding activity in LPS-stimulated BV2 microglia. Therefore, the study suggests that nanosized TiO₂NPs promote exaggerated neuroinflammatory responses by activating microglia. In line with this, another study found that LPS-activated BV-2 cells took more TiO₂NPs up compared to non-activated cells, leading to increased IL-6, ROS, MCP-1, and IL-1β.¹⁶¹ Along with it, Xue et al.¹⁶² showed that TiO₂NPs induced significant iNOS expression and subsequent NO secretion, accompanied by upregulation of chemokines through NF-κB activation in NP-stimulated microglia in vitro. This study also indicated raised levels of pro-inflammatory cytokines.

To conclude, TiO₂NPs activate microglia and neuroinflammation using various pathways. Given the small number of papers written on TiO₂NPs and the scarcity of positive findings, additional research is essential to comprehensively understand the mechanisms in charge of the harmful effects of TiO₂NPs on microglia-related neuroinflammation. These findings will facilitate the evolution of strategies for the secure and efficient employment of TiO₂NPs in the treatment of neurodegenerative diseases.

6.7. Silica nanoparticles (SiO₂NPs)/Silicon nanoparticles (SiNPs)

Silica nanoparticles (SiO₂NPs), one of the most widely employed types of NPs, have been applied across various industries.¹⁶³ Nanosized SiO₂ can cross the BBB, making them valuable for delivering therapeutic and diagnostic agents.¹⁶⁴ The exposure to SiO₂ does not significantly influence the viability of various neural cells, and it also does not cause neuroinflammation.¹⁶⁵ However, long-term exposure to these NPs can cause cognitive impairment, mood dysfunction, and synaptic alterations, potentially by activating mitogen-activated protein kinases (MAPKs).¹⁶⁶ Therefore, the potential of SiO₂NPs for treating microglia-induced neuroinflammation merits further exploration.

SiO₂NPs have shown potential in activating microglia. In line with this, in a study, after exposure to fluorescein isothiocyanate-tagged SiO₂NPs (FITC-SiO₂-NPs),^167,168 the number of Iba-1- stained microglia significantly rose in the hippocampus in comparison with the controls.¹⁶⁶ Consistently, a study showed that silica-coated magnetic NPs containing rhodamine B isothiocyanate dye (MNPs@SiO₂(RITC)) morphologically activated BV2 murine microglia and increased Iba1 expression, an activation marker protein.¹⁶⁹ The study also demonstrated that microglia activation elevated serine protein levels in the growth medium. Notably, the secretion of excitotoxic D-serine from primary rat microglia was significantly upregulated, which in turn decreased intracellular ATP and activity of the proteasome in cocultured neuronal cells, particularly in primary cortical neurons. This led to the accumulation of ubiquitinated proteins and the formation of inclusion bodies in cortical and primary dopaminergic neurons cocultured with activated microglia. Thus, the activation of microglia by MNPs@SiO₂(RITC) initiates excitotoxicity in neurons through the secretion of D-serine, underscoring the neurotoxic processes triggered by microglial activation.¹⁵⁶ SiO2NPs are likely to produce inflammatory agents and cause neuroinflammation. In this way, Xue et al. demonstrated that SiO₂NPs enhance the proinflammatory cytokines (TNF-α, IL-1β, and IL-6).¹⁶² Additionally, the findings of another study illustrated that deficient SiNP levels could change microglial function. In turn, alteration in proinflammatory genes, cytokine release, and heightened RNS and ROS production adversely affect not only microglial function but also surrounding neurons.¹⁷⁰ Correspondingly, MNPs@SiO₂(RITC) were shown by another study to enhance ROS production in a dose-dependent manner.¹⁷¹ The findings of another research indicated that the viability of MNPs@SiO₂(RITC) was gradually reduced with increasing SiO₂NP concentration and exposure duration. The findings indicated that SiNPs could penetrate the cytoplasm, alter the ultrastructure, activate the NLRP3 inflammasome, release a multitude of inflammatory molecules, and start inflammatory reactions. SiNPs were also discovered to induce ferroptosis, increase intracellular ferrous ion levels, and disrupt cellular antioxidant function.¹⁷⁰

In summary, the studies reviewed suggest that SiO₂NPs possess the potential to induce microglial activation and neuroinflammation, negatively impacting neuronal health. Due to the scarcity of studies on the positive influences of these NPs on microglia-related neuroinflammation, the potential of SiO₂NPs for treating neuroinflammation deserves further research to fully elucidate the risks of exploiting this nanoparticle.

Regarding the explained studies, Fig. 4 illustrates the advantages and disadvantages of each metal NP in the inhibition of microglia-mediated neuroinflammation.

Fig. 4 The advantages and disadvantages of drug-loaded metal NPs in microglia-induced neuroinflammation.

7. Conclusion

Microglia are central to neuroinflammation and neurodegeneration, capable of both protecting and harming the CNS. Metal nanoparticles offer exciting potential for targeting microglial activity due to their ability to cross the BBB and move medicines directly to the brain. However, their dual effects, ranging from neuroprotection to exacerbation of inflammation, necessitate careful consideration. While AuNPs and certain IONPs show promise in reducing neuroinflammation, other NPs like AgNPs, ZnONPs, and TiO₂NPs have been linked to increased neurotoxicity. As the field progresses, future research is proposed to focus on deciphering the specific mechanisms underlying nanoparticle–microglia interactions, paving the way for targeted and safe interventions for neurodegenerative diseases. A comprehensive understanding of these interactions will enhance the therapeutic potential of nanoparticles and ensure neural homeostasis. In this dynamic landscape, interdisciplinary collaboration and continued exploration are essential to address these challenges and unlock the full therapeutic potential of nanoparticles in neurodegenerative disorders.

8. Challenges

Despite the promising potential of metal nanoparticles (NPs) in treating neuroinflammation and modulating microglial activity, several critical challenges remain.

8.1. Toxicity and biocompatibility

The biocompatibility of NPs is a key factor in their clinical translation. Although some NPs, such as gold nanoparticles (AuNPs), are considered relatively safe, others, like silver nanoparticles (AgNPs), can induce oxidative stress and pro-inflammatory responses in microglial cells at higher concentrations. The dose-dependent duality of these effects necessitates precise dose optimization and the development of biocompatible coatings to mitigate toxicity.

8.2. Blood–brain barrier (BBB) permeability

While the nanoscale size of certain NPs facilitates their ability to cross the BBB, their transport efficiency and distribution in targeted brain regions remain inconsistent. Surface charge, hydrophilicity, and interactions with serum proteins can impact their BBB permeability and bioavailability, limiting therapeutic outcomes.

8.3. Stability in biological environments

The physicochemical stability of NPs in the dynamic and complex CNS environment is a significant challenge. Non-functionalized NPs are prone to aggregation and premature clearance, while improperly stabilized particles may lose activity before reaching their target. Effective functionalization strategies are required to enhance stability, circulation time, and targeted delivery.

8.4. Long-term safety and accumulation

The long-term effects of NPs, including potential accumulation in brain tissues, remain poorly understood. Chronic exposure could lead to neurotoxicity, inflammation, or immune system interference. Comprehensive in vivo studies are needed to evaluate their safety profiles under prolonged use.

8.5. Immune system interactions

NPs may inadvertently activate peripheral or central immune responses, complicating their therapeutic use. Understanding and mitigating these interactions is critical for reducing adverse effects and enhancing therapeutic specificity.

9. Future perspective

9.1. Development of advanced nanoparticle designs

The engineering of next-generation NPs with precise targeting capabilities is paramount. Functionalization with ligands specific to inflammatory markers or activated microglia can enhance therapeutic specificity while reducing off-target effects. Stimuli-responsive NPs that release their therapeutic payload in response to pH, temperature, or inflammatory signals could provide controlled and localized treatment.

9.2. Exploration of biodegradable nanoparticles

The development of biodegradable NPs that degrade into non-toxic byproducts after delivering their cargo is crucial for minimizing long-term risks. Materials such as polymers, lipid-based carriers, or naturally derived compounds should be further explored to ensure both efficacy and safety.

9.3. Combination therapies

Leveraging the co-delivery capabilities of NPs to carry multiple therapeutic agents, such as anti-inflammatory drugs, antioxidants, or gene therapy vectors, can target multiple pathways simultaneously. These approaches could provide synergistic effects, particularly in complex disorders like Alzheimer's disease or Parkinson's disease.

9.4. In-depth mechanistic studies

Detailed studies on the molecular mechanisms of NP-microglia interactions are essential. Investigating how NPs influence microglial polarization between pro-inflammatory (M1) and anti-inflammatory (M2) states can guide the design of more effective therapeutic strategies.

9.5. Preclinical and clinical translation

Long-term safety, pharmacokinetics, and efficacy studies in animal models are vital for bridging the gap between preclinical research and clinical application. Establishing standardized protocols for NP synthesis, characterization, and biological testing will also facilitate regulatory approval and clinical trials.

9.6. Interdisciplinary collaboration

The successful translation of NP-based therapies requires collaboration across disciplines, including materials science, neuroscience, pharmacology, and toxicology. Integrating advanced imaging, computational modeling, and machine learning techniques can accelerate NP design and optimize therapeutic outcomes.

By addressing these challenges and exploring these prospective directions, nanoparticle-based therapies could revolutionize the treatment of neuroinflammation and related CNS disorders.

List of abbreviations

CNS	Central nervous system
AuNP	Gold nanoparticle
AgNP	Silver nanoparticle
IONP	Iron oxide nanoparticle
SiO2NP	Silica nanoparticle
ZnONP	Zinc oxide nanoparticle
CoNP	Cobalt nanoparticle
TiO2NP	Titanium oxide nanoparticle
TNF-α	Tumour necrosis factor alpha
DAMPs	Danger-associated molecular patterns
PGE2	Prostaglandin E2
PAMPs	Pathogen-associated molecular patterns
CR and CR	Complement receptors
CD	Cluster of differentiation
IL	Interleukin
ROS	Reactive oxygen species
TLR and TLR	Toll-like receptors
BACE	Beta-secretase enzyme
iNOS	Inducible nitric oxide synthase
COX2	Cyclooxygenase-2
BBB	Blood–brain-barrier
ECM	Extracellular matrix
NPs	Nanoparticles
TGN	Trans-Golgi network
Iba-1	Ionized calcium-binding adapter molecule
ALTs	Astrocyte-like
N2a	Neuro2a
NF-κB	Nuclear factor-κB
SPIONPs	Superparamagnetic iron oxide nanoparticles
MPI	Magnetic particle imaging
DHLA	Dihydrolipoic acid
FIB	Fibrinogen
BS	Bovine serum
PC	Protein corona
JAK/STAT	Janus kinase/signal transducers and activators of transcription
PEGylated AuNPs	polyethyleneglycol-coupled AuNPs
PM-AuNPs	Paeonia moutan to functionalize GNPs
CeO2NPs	Cerium oxide nanoparticles
Aβ	Amyloid-β
GSS	Glutathione synthetase
AD	Alzheimer's disease
MMP	Matrix metalloproteinases
AnPEG-GNPs	Anthocyanins conjugated with PEG-GNPs
MAPKs	Mitogen-activated protein kinases
MARCO	Macrophage receptor with collagenous structure
FITC	Fluorescein isothiocyanate
ERK	Extracellular signal-regulated kinase

Data availability

This article does not include primary research data, software, or code. It is a review article that discusses findings from various studies in the field with all data and figures cited from previously published sources. No new data were generated or analyzed in the preparation of this article.

Author contributions

Masood Alaei, Khadijeh Koushki, and Kimia Taebi contributed to the conceptualization and methodology, collected data, and drafted the manuscript. Masood Alaei illustrated the figures and charts. Mahdieh Yousefi Taba and Samaneh Keshavarz Hedayati co-operated in writing and drafting the manuscript. Sanaz Keshavarz Shahbaz participated in supervising, providing critical review, commentary, and revising the final draft of the manuscript.

Conflicts of interest

All the authors declare no conflicts of interest related to this manuscript.

Acknowledgements

This work was supported by Qazvin University of Medical Sciences.

References

1. A. Adamu, S. Li, F. Gao and G. Xue, The role of neuroinflammation in neurodegenerative diseases: current understanding and future therapeutic targets, Front. Aging Neurosci., 2024, 16, 1347987.
2. S. S. Keshavarz, K. Koushki, S. Keshavarz Hedayati, A. P. McCloskey, P. Kesharwani and Y. Naderi, et al., Polymer nanotherapeutics: A promising approach toward microglial inhibition in neurodegenerative diseases, Med. Res. Rev., 2024, 44(6), 2793–2824.
3. T. Sun, Y. S. Zhang, B. Pang, D. C. Hyun and M. Y. Yang, Xia Engineered nanoparticles for drug delivery in cancer therapy, Angew. Chem., Int. Ed., 2014, 53, 12320–12364.
4. E. Hutter, S. Boridy, S. Labrecque, M. Lalancette-Hébert, J. Kriz and F. M. Winnik, et al., Microglial response to gold nanoparticles, ACS Nano, 2010, 4(5), 2595–2606.
5. A. Joseph, R. Liao, M. Zhang, H. Helmbrecht, M. McKenna and J. R. Filteau, et al., Nanoparticle-microglial interaction in the ischemic brain is modulated by injury duration and treatment, Bioeng. Transl. Med., 2020, 5(3), e10175.
6. M. Prinz, T. Masuda, M. A. Wheeler and F. J. Quintana, Microglia and Central Nervous System-Associated Macrophages-From Origin to Disease Modulation, Annu. Rev. Immunol., 2021, 39, 251–277.
7. L. C. Mehl, A. V. Manjally, O. Bouadi, E. M. Gibson and T. L. Tay, Microglia in brain development and regeneration, Development, 2022, 149(8), dev200425.
8. V. H. Perry and J. Teeling, Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration, Semin. Immunopathol., 2013, 35(5), 601–612.
9. S. Bilbo and B. Stevens, Microglia: The Brain's First Responders, Cerebrum, 2017, cer-14-17.
10. M. Colonna and O. Butovsky, Microglia Function in the Central Nervous System During Health and Neurodegeneration, Annu. Rev. Immunol., 2017, 35, 441–468.
11. Y.-L. Tan, Y. Yuan and L. Tian, Microglial regional heterogeneity and its role in the brain, Mol. Psychiatry, 2020, 25(2), 351–367.
12. X. Chang, J. Li, S. Niu, Y. Xue and M. Tang, Neurotoxicity of metal-containing nanoparticles and implications in glial cells, J. Appl. Toxicol., 2021, 41(1), 65–81.
13. D. M. Angelova and D. R. Brown, Microglia and the aging brain: are senescent microglia the key to neurodegeneration?, J. Neurochem., 2019, 151(6), 676–688.
14. N. J. Allen and D. A. Lyons, Glia as architects of central nervous system formation and function, Science, 2018, 362(6411), 181–185.
15. S. Jäkel and L. Dimou, Glial Cells and Their Function in the Adult Brain: A Journey through the History of Their Ablation, Front. Cell. Neurosci., 2017, 11, 14.
16. G. C. Brown and J. J. Neher, Microglial phagocytosis of live neurons, Nat. Rev. Neurosci., 2014, 15(4), 209–216.
17. A. N. Hughes and B. Appel, Microglia phagocytose myelin sheaths to modify developmental myelination, Nat. Neurosci., 2020, 23(9), 1055–1066.
18. R. Fu, Q. Shen, P. Xu, J. J. Luo and Y. Tang, Phagocytosis of microglia in the central nervous system diseases, Mol. Neurobiol., 2014, 49(3), 1422–1434.
19. C. Herzog, L. Pons Garcia, M. Keatinge, D. Greenald, C. Moritz and F. Peri, et al., Rapid clearance of cellular debris by microglia limits secondary neuronal cell death after brain injury in vivo, Development, 2019, 146(9), dev174698.
20. S. Guo, H. Wang and Y. Yin, Microglia Polarization From M1 to M2 in Neurodegenerative Diseases, Front. Aging Neurosci., 2022, 14, 815347.
21. S. Kobashi, T. Terashima, M. Katagi, Y. Nakae, J. Okano and Y. Suzuki, et al., Transplantation of M2-Deviated Microglia Promotes Recovery of Motor Function after Spinal Cord Injury in Mice, Mol. Ther., 2020, 28(1), 254–265.
22. S. R. Subramaniam and H. J. Federoff, Targeting Microglial Activation States as a Therapeutic Avenue in Parkinson’s Disease, Front. Aging Neurosci., 2017, 9, 176.
23. N. Zhao, N. L. Francis, H. R. Calvelli and P. V. Moghe, Microglia-targeting nanotherapeutics for neurodegenerative diseases, APL Bioeng., 2020, 4(3), 030902.
24. S. Bachiller, I. Jiménez-Ferrer, A. Paulus, Y. Yang, M. Swanberg and T. Deierborg, et al., Microglia in neurological diseases: a road map to brain-disease dependent-inflammatory response, Front. Cell. Neurosci., 2018, 12, 488.
25. G. J. Harry, Microglia in Neurodegenerative Events-An Initiator or a Significant Other?, Int. J. Mol. Sci., 2021, 22(11), 5818.
26. J.-W. Lee, W. Chun, H. J. Lee, S.-M. Kim, J.-H. Min and D.-Y. Kim, et al., The Role of Microglia in the Development of Neurodegenerative Diseases, Biomedicines, 2021, 9(10), 1449.
27. M. E. Lull and M. L. Block, Microglial Activation and Chronic Neurodegeneration, Neurotherapeutics, 2010, 7(4), 354–365.
28. D. Doens and P. L. Fernández, Microglia receptors and their implications in the response to amyloid β for Alzheimer's disease pathogenesis, J. Neuroinflammation, 2014, 11(1), 1–14.
29. G. Sita, A. Graziosi, P. Hrelia and F. Morroni, NLRP3 and Infections: β-Amyloid in Inflammasome beyond Neurodegeneration, Int. J. Mol. Sci., 2021, 22(13), 6984.
30. G. Zhang, Z. Wang, H. Hu, M. Zhao and L. Sun, Microglia in Alzheimer's disease: A target for therapeutic intervention, Front. Cell. Neurosci., 2021, 15, 749587.
31. C. Xing and E. H. Lo, Help-me signaling: Non-cell autonomous mechanisms of neuroprotection and neurorecovery, Prog. Neurobiol., 2017, 152, 181–199.
32. R. Von Bernhardi, L. Eugenín-von Bernhardi and J. Eugenín, Microglial cell dysregulation in brain aging and neurodegeneration, Front. Aging Neurosci., 2015, 7, 124.
33. R. A. Feldman, Microglia orchestrate neuroinflammation, Elife, 2022, 11, e81890.
34. G. C. Brown and A. Vilalta, How microglia kill neurons, Brain Res., 2015, 1628, 288–297.
35. U.-K. Hanisch and H. Kettenmann, Microglia: active sensor and versatile effector cells in the normal and pathologic brain, Nat. Neurosci., 2007, 10(11), 1387–1394.
36. H. S. Kwon and S.-H. Koh, Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes, Transl. Neurodegener., 2020, 9, 1–12.
37. D. K. Choi, S. Koppula and K. Suk, Inhibitors of microglial neurotoxicity: focus on natural products, Molecules, 2011, 16(2), 1021–1043.
38. S. K. Maurya, N. Bhattacharya, S. Mishra, A. Bhattacharya, P. Banerjee and S. Senapati, et al., Microglia specific drug targeting using natural products for the regulation of redox imbalance in neurodegeneration, Front. Pharmacol, 2021, 12, 654489.
39. C.-Y. Liu, X. Wang, C. Liu and H.-L. Zhang, Pharmacological targeting of microglial activation: new therapeutic approach, Front. Cell. Neurosci., 2019, 13, 514.
40. Y. S. Gwak, E. D. Crown, G. C. Unabia and C. E. Hulsebosch, Propentofylline attenuates allodynia, glial activation and modulates GABAergic tone after spinal cord injury in the rat, Pain, 2008, 138(2), 410–422.
41. A. V. A. David, R. Arulmoli and S. Parasuraman, Overviews of biological importance of quercetin: A bioactive flavonoid, Pharmacogn. Rev., 2016, 10(20), 84.
42. M. Nikodemova, J. J. Watters, S. J. Jackson, S. K. Yang and I. D. Duncan, Minocycline down-regulates MHC II expression in microglia and macrophages through inhibition of IRF-1 and protein kinase C (PKC) α/βII, J. Biol. Chem., 2007, 282(20), 15208–15216.
43. R. Z. Hamza and N. S. El-Shenawy, Anti-inflammatory and antioxidant role of resveratrol on nicotine-induced lung changes in male rats, Toxicol. Rep., 2017, 4, 399–407.
44. T. Farkhondeh, S. L. Folgado, A. M. Pourbagher-Shahri, M. Ashrafizadeh and S. Samarghandian, The therapeutic effect of resveratrol: Focusing on the Nrf2 signaling pathway, Biomed. Pharmacother., 2020, 127, 110234.
45. C. Y. Chang, D.-K. Choi, D. K. Lee, Y. J. Hong and E. J. Park, Resveratrol confers protection against rotenone-induced neurotoxicity by modulating myeloperoxidase levels in glial cells, PLoS One, 2013, 8(4), e60654.
46. Y. Yu, Q. Shen, Y. Lai, S. Y. Park, X. Ou and D. Lin, et al., Anti-inflammatory effects of curcumin in microglial cells, Front. Pharmacol., 2018, 9, 386.
47. T. Akaishi, S. Yamamoto and K. Abe, The Synthetic Curcumin Derivative CNB-001 Attenuates Thrombin-Stimulated Microglial Inflammation by Inhibiting the ERK and p38 MAPK Pathways, Biol. Pharm. Bull., 2020, 43(1), 138–144.
48. Y. Han, R. Chen, Q. Lin, Y. Liu, W. Ge and H. Cao, et al., Curcumin improves memory deficits by inhibiting HMGB1-RAGE/TLR4-NF-κB signalling pathway in APPswe/PS1dE9 transgenic mice hippocampus, J. Cell. Mol. Med., 2021, 25(18), 8947–8956.
49. A. Khan, T. Ali, S. U. Rehman, M. S. Khan, S. I. Alam and M. Ikram, et al., Neuroprotective effect of quercetin against the detrimental effects of LPS in the adult mouse brain, Front. Pharmacol, 2018, 9, 1383.
50. J. Bournival, M. Plouffe, J. Renaud, C. Provencher and M.-G. Martinoli, Quercetin and sesamin protect dopaminergic cells from MPP+-induced neuroinflammation in a microglial (N9)-neuronal (PC12) coculture system, Oxid. Med. Cell. Longevity, 2012, 2012, 921941.
51. Y. Naderi, M. Sabetkasaei, S. Parvardeh and T. Moini Zanjani, Neuroprotective effects of pretreatment with minocycline on memory impairment following cerebral ischemia in rats, Behav. Pharmacol., 2017, 28(2), 214–222.
52. Y. Naderi, M. Sabetkasaei, S. Parvardeh and T. M. Zanjani, Neuroprotective effect of minocycline on cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory and anti-oxidant properties in male rat, Brain Res. Bull., 2017, 131, 207–213.
53. T. Patel, J. Zhou, J. M. Piepmeier and W. M. Saltzman, Polymeric nanoparticles for drug delivery to the central nervous system, Adv. Drug Delivery Rev., 2012, 64(7), 701–705.
54. C. A. Peptu, L. Ochiuz, L. Alupei, C. Peptu and M. Popa, Carbohydrate based nanoparticles for drug delivery across biological barriers, J. Biomed. Nanotechnol., 2014, 10(9), 2107–2148.
55. S. Cramer, R. Rempe and H.-J. Galla, Exploiting the properties of biomolecules for brain targeting of nanoparticulate systems, Curr. Med. Chem., 2012, 19(19), 3163–3187.
56. R. Ansari, S. M. Sadati, N. Mozafari, H. Ashrafi and A. Azadi, Carbohydrate polymer-based nanoparticle application in drug delivery for CNS-related disorders, Eur. Polym. J., 2020, 128, 109607.
57. A. Armulik, G. Genové, M. Mäe, M. H. Nisancioglu, E. Wallgard and C. Niaudet, et al., Pericytes regulate the blood–brain barrier, Nature, 2010, 468(7323), 557–561.
58. W. M. Pardridge, Drug targeting to the brain, Pharm. Res., 2007, 24, 1733–1744.
59. W. A. Banks and N. H. Greig, Small molecules as central nervous system therapeutics: old challenges, new directions, and a philosophic divide, Future Sci. OA, 2019, 489–493.
60. W. M. Pardridge, Drug transport across the blood–brain barrier, J. Cereb. Blood Flow Metab., 2012, 32(11), 1959–1972.
61. J. Song, C. Lu, J. Leszek and J. Zhang, Design and development of nanomaterial-based drug carriers to overcome the blood–brain barrier by using different transport mechanisms, Int. J. Mol. Sci., 2021, 22(18), 10118.
62. S. R. Hwang and K. Kim, Nano-enabled delivery systems across the blood–brain barrier, Arch. Pharmacal Res., 2014, 37(1), 24–30.
63. K. Matsuhisa, M. Kondoh, A. Takahashi and K. Yagi, Tight junction modulator and drug delivery, Expert Opin. Drug Delivery, 2009, 6(5), 509–515.
64. E. Nance, S. H. Pun, R. Saigal and D. L. Sellers, Drug delivery to the central nervous system, Nat. Rev. Mater., 2022, 7(4), 314–331.
65. C. Ekhator, M. Q. Qureshi, A. W. Zuberi, M. Hussain, N. Sangroula and S. Yerra, et al., Advances and Opportunities in Nanoparticle Drug Delivery for Central Nervous System Disorders: A Review of Current Advances, Cureus, 2023, 15(8), e44302.
66. J. A. Morris, C. H. Boshoff, N. F. Schor, L. M. Wong, G. Gao and B. L. Davidson, Next-generation strategies for gene-targeted therapies of central nervous system disorders: A workshop summary, Mol. Ther., 2021, 29(12), 3332–3344.
67. A. Sintov, C. Velasco, E. Gallardo-Toledo and E. Araya, Metal Nanoparticles as Targeted Carriers Circumventing the Blood–Brain Barrier, Int. Rev. Neurobiol., 2016, 199–227.
68. A. M. Hersh, S. Alomari and B. M. Tyler, Crossing the Blood–Brain Barrier: Advances in Nanoparticle Technology for Drug Delivery in Neuro-Oncology, Int. J. Mol. Sci., 2022, 23(8), 4153.
69. L. A. Bors and F. Erdő, Overcoming the blood–brain barrier. challenges and tricks for CNS drug delivery, Sci. Pharm., 2019, 87(1), 6.
70. T. Siegal, Which drug or drug delivery system can change clinical practice for brain tumor therapy?, Neuro-Oncology, 2013, 15(6), 656–669.
71. J. Kim, S. I. Ahn and Y. Kim, Nanotherapeutics engineered to cross the blood–brain barrier for advanced drug delivery to the central nervous system, J. Ind. Eng. Chem., 2019, 73, 8–18.
72. E. Calzoni, A. Cesaretti, A. Polchi, A. Di Michele, B. Tancini and C. Emiliani, Biocompatible polymer nanoparticles for drug delivery applications in cancer and neurodegenerative disorder therapies, J. Funct. Biomater., 2019, 10(1), 4.
73. C. Medina, M. Santos-Martinez, A. Radomski, O. Corrigan and M. Radomski, Nanoparticles: pharmacological and toxicological significance, Br. J. Pharmacol., 2007, 150(5), 552–558.
74. K. A. Altammar, A review on nanoparticles: characteristics, synthesis, applications, and challenges, Front Microbiol., 2023, 14, 1155622.
75. T. Wu and M. Tang, The inflammatory response to silver and titanium dioxide nanoparticles in the central nervous system, Nanomedicine, 2018, 13(2), 233–249.
76. L. Zhou, Y. Wu, X. Meng, S. Li, J. Zhang and P. Gong, et al., Dye-Anchored MnO Nanoparticles Targeting Tumor and Inducing Enhanced Phototherapy Effect via Mitochondria-Mediated Pathway, Small, 2018, 14(36), 1801008.
77. H. Gao, J. Qian, S. Cao, Z. Yang, Z. Pang and S. Pan, et al., Precise glioma targeting of and penetration by aptamer and peptide dual-functioned nanoparticles, Biomaterials, 2012, 33(20), 5115–5123.
78. W. Zhang, R. Taheri-Ledari, F. Ganjali, S. S. Mirmohammadi, F. S. Qazi and M. Saeidirad, et al., Effects of morphology and size of nanoscale drug carriers on cellular uptake and internalization process: a review, RSC Adv., 2022, 13(1), 80–114.
79. R. Mout, D. F. Moyano, S. Rana and V. M. Rotello, Surface functionalization of nanoparticles for nanomedicine, Chem. Soc. Rev., 2012, 41(7), 2539–2544.
80. N. Zhao, N. L. Francis, H. R. Calvelli and P. V. Moghe, Microglia-targeting nanotherapeutics for neurodegenerative diseases, APL Bioeng., 2020, 4(3), 030902.
81. M. Blank, T. Enzlein and C. Hopf, LPS-induced lipid alterations in microglia revealed by MALDI mass spectrometry-based cell fingerprinting in neuroinflammation studies, Sci. Rep., 2022, 12(1), 2908.
82. C. Qiu, F. Xia, J. Zhang, Q. Shi, Y. Meng and C. Wang, et al. Advanced Strategies for Overcoming Endosomal/Lysosomal Barrier in Nanodrug Delivery. Research, Wash D C. 2023;6:p. 0148.
83. J. Du, L. A. Lane and S. Nie, Stimuli-responsive nanoparticles for targeting the tumor microenvironment, J. Controlled Release, 2015, 219, 205–214.
84. P. Davoodi, L. Y. Lee, Q. Xu, V. Sunil, Y. Sun and S. Soh, et al., Drug delivery systems for programmed and on-demand release, Adv. Drug Delivery Rev., 2018, 132, 104–138.
85. H. Zhu, H. Chen, X. Zeng, Z. Wang, X. Zhang and Y. Wu, et al., Co-delivery of chemotherapeutic drugs with vitamin E TPGS by porous PLGA nanoparticles for enhanced chemotherapy against multi-drug resistance, Biomaterials, 2014, 35(7), 2391–2400.
86. Q. Feng, Y. Shen, Y. Fu, M. E. Muroski, P. Zhang and Q. Wang, et al., Self-assembly of gold nanoparticles shows microenvironment-mediated dynamic switching and enhanced brain tumor targeting, Theranostics, 2017, 7(7), 1875.
87. Y. Zhu, J. Feijen and Z. Zhong, Dual-targeted nanomedicines for enhanced tumor treatment, Nano Today, 2018, 18, 65–85.
88. X. Dong, Current strategies for brain drug delivery, Theranostics, 2018, 8(6), 1481.
89. W. H. Chen, G. F. Luo and X. Z. Zhang, Recent advances in subcellular targeted cancer therapy based on functional materials, Adv. Mater., 2019, 31(3), 1802725.
90. Y. Ju-Nam and J. R. Lead, Manufactured nanoparticles: An overview of their chemistry, interactions and potential environmental implications, Sci. Total Environ., 2008, 400(1), 396–414.
91. C. Bai and M. Tang, Toxicological study of metal and metal oxide nanoparticles in zebrafish, J. Appl. Toxicol., 2020, 40(1), 37–63.
92. X. Chang, J. Li, S. Niu, Y. Xue and M. Tang, Neurotoxicity of metal-containing nanoparticles and implications in glial cells, J. Appl. Toxicol., 2021, 41(1), 65–81.
93. V. Kumar, Toll-like receptors in the pathogenesis of neuroinflammation, J. Neuroimmunol., 2019, 332, 16–30.
94. D. S. A. Simpson and P. L. Oliver, ROS Generation in Microglia: Understanding Oxidative Stress and Inflammation in Neurodegenerative Disease, Antioxidants, 2020, 9(8), 743.
95. M. Battaglini, A. Marino, M. Montorsi, A. Carmignani, M. C. Ceccarelli and G. Ciofani, Nanomaterials as Microglia Modulators in the Treatment of Central Nervous System Disorders, Adv. Healthcare Mater., 2024, 13(12), 2304180.
96. X. Feng, A. Chen, Y. Zhang, J. Wang, L. Shao and L. Wei, Central nervous system toxicity of metallic nanoparticles, Int. J. Nanomed., 2015, 4321–4340.
97. M. Tareq, Y. A. Khadrawy, M. M. Rageh and H. S. Mohammed, Dose-dependent biological toxicity of green synthesized silver nanoparticles in rat's brain, Sci. Rep., 2022, 12(1), 22642.
98. A. A. Antsiferova, M. Y. Kopaeva, V. N. Kochkin, A. A. Reshetnikov and P. K. Kashkarov, Neurotoxicity of silver nanoparticles and non-linear development of adaptive homeostasis with age, Micromachines, 2023, 14(5), 984.
99. C. M. Duffy, S. Ahmed, C. Yuan, V. Mavanji, J. P. Nixon and T. Butterick, Microglia as a Surrogate Biosensor to Determine Nanoparticle Neurotoxicity, J. Visualized Exp., 2016,(116), 54662.
100. C.-L. Huang, I.-L. Hsiao, H.-C. Lin, C.-F. Wang, Y.-J. Huang and C.-Y. Chuang, Silver nanoparticles affect on gene expression of inflammatory and neurodegenerative responses in mouse brain neural cells, Environ. Res., 2015, 136, 253–263.
101. L. Xiao, F. Wei, Y. Zhou, G. J. Anderson, D. M. Frazer and Y. C. Lim, et al., Dihydrolipoic acid–gold nanoclusters regulate microglial polarization and have the potential to alter neurogenesis, Nano Lett., 2019, 20(1), 478–495.
102. M. C. Hohnholt, M. Geppert, E. M. Luther, C. Petters, F. Bulcke and R. Dringen, Handling of iron oxide and silver nanoparticles by astrocytes, Neurochem. Res., 2013, 38(2), 227–239.
103. R. Yokel, E. Grulke and R. MacPhail, Metal-based nanoparticle interactions with the nervous system: the challenge of brain entry and the risk of retention in the organism, Wiley Interdiscip. Rev.:Nanomed. Nanobiotechnol., 2013, 5(4), 346–373.
104. J. Milan, K. Niemczyk and M. Kus-Liśkiewicz, Treasure on the Earth—Gold Nanoparticles and Their Biomedical Applications, Materials, 2022, 15(9), 3355.
105. H.-H. Jeong, E. Choi, E. Ellis and T.-C. Lee, Recent advances in gold nanoparticles for biomedical applications: from hybrid structures to multi-functionality, J. Mater. Chem. B, 2019, 7(22), 3480–3496.
106. C. Su, K. Huang, H.-H. Li, Y.-G. Lu and D.-L. Zheng, Antibacterial properties of functionalized gold nanoparticles and their application in oral biology, J. Nanomater., 2020, 2020(1), 5616379.
107. S. Chawla, N. Kerna, N. Carsrud, K. Pruitt, J. Flores, H. Holets and N. J. Obi, et al., Revealing the Health Applica-tions of Gold Nanoparticles for the Cardiovascular System (and in Nerve, Bone, Immune, Skin, and Mental Disorders), EC Cardiology, 2023, 10, 09–23.
108. L. A. Dykman and N. G. Khlebtsov, Gold nanoparticles in biology and medicine: recent advances and prospects, Acta Naturae, 2011, 3(2), 34–55.
109. K. Koushki, S. Keshavarz Shahbaz, M. Keshavarz, E. E. Bezsonov, T. Sathyapalan and A. Sahebkar, Gold nanoparticles: Multifaceted roles in the management of autoimmune disorders, Biomolecules, 2021, 11(9), 1289.
110. Z. D. Ozdal, E. Sahmetlioglu, I. Narin and A. Cumaoglu, Synthesis of gold and silver nanoparticles using flavonoid quercetin and their effects on lipopolysaccharide induced inflammatory response in microglial cells, 3 Biotech, 2019, 9(6), 1–8.
111. I. Kuschnerus, M. Lau, K. Giri, N. Bedford, J. Biazik and J. Ruan, et al., Effect of a protein corona on the fibrinogen induced cellular oxidative stress of gold nanoparticles, Nanoscale, 2020, 12(10), 5898–5905.
112. S. Y. Park, E. H. Yi, Y. Kim and G. Park, Anti-neuroinflammatory effects of Ephedra sinica Stapf extract-capped gold nanoparticles in microglia, Int. J. Nanomed., 2019, 2861–2877.
113. E. Lira-Diaz, M. G. Gonzalez-Pedroza, C. Vasquez, R. A. Morales-Luckie and O. Gonzalez-Perez, Gold nanoparticles produce transient reactive gliosis in the adult brain, Neurosci. Res., 2021, 76–86.
114. E. Hutter, S. Boridy, S. Labrecque, M. Lalancette-Hébert, J. Kriz and F. M. Winnik, et al., Microglial response to gold nanoparticles, ACS Nano, 2010, 4(5), 2595–2606.
115. J. Xue, T. Liu, Y. Liu, Y. Jiang, V. D. D. Seshadri and S. K. Mohan, et al., Neuroprotective effect of biosynthesised gold nanoparticles synthesised from root extract of Paeonia moutan against Parkinson disease–In vitro & In vivo model, J. Photochem. Photobiol., B, 2019, 200, 111635.
116. N. Zhao, X. Yang, H. R. Calvelli, Y. Cao, N. L. Francis and R. A. Chmielowski, et al., Antioxidant nanoparticles for concerted inhibition of α-synuclein fibrillization, and attenuation of microglial intracellular aggregation and activation, Front. Bioeng. Biotechnol., 2020, 8, 112.
117. M.-J. Wang, H.-Y. Huang, W.-F. Chen, H.-F. Chang and J.-S. Kuo, Glycogen synthase kinase-3β inactivation inhibits tumor necrosis factor-α production in microglia by modulating nuclear factor κB and MLK3/JNK signaling cascades, J. Neuroinflammation, 2010, 7(1), 99.
118. M. J. Kim, S. U. Rehman, F. U. Amin and M. O. Kim, Enhanced neuroprotection of anthocyanin-loaded PEG-gold nanoparticles against Aβ1-42-induced neuroinflammation and neurodegeneration via the NF-κB/JNK/GSK3β signaling pathway, Nanomed. Nanotechnol. Biol. Med., 2017, 13(8), 2533–2544.
119. G. Aliev, J. Daza, A. Solís Herrera, M. del Carmen Arias Esparza, L. Morales and V. Echeverria, et al., Nanoparticles as alternative strategies for drug delivery to the Alzheimer brain: electron microscopy ultrastructural analysis, CNS Neurol Disord Drug Targets, 2015, 14(9), 1235–1242.
120. M. R. Pickard and D. M. Chari, Robust uptake of magnetic nanoparticles (MNPs) by central nervous system (CNS) microglia: implications for particle uptake in mixed neural cell populations, Int. J. Mol. Sci., 2010, 11(3), 967–981.
121. I. L. Hsiao, Y. K. Hsieh, C. Y. Chuang, C. F. Wang and Y. J. Huang, Effects of silver nanoparticles on the interactions of neuron-and glia-like cells: Toxicity, uptake mechanisms, and lysosomal tracking, Environ. Toxicol.:Princ. Policies, 2017, 32(6), 1742–1753.
122. C. Sun, N. Yin, R. Wen, W. Liu, Y. Jia and L. Hu, et al., Silver nanoparticles induced neurotoxicity through oxidative stress in rat cerebral astrocytes is distinct from the effects of silver ions, Neurotoxicology, 2016, 52, 210–221.
123. S. Amiri, A. Yousefi-Ahmadipour, M.-J. Hosseini, A. Haj-Mirzaian, M. Momeny and H. Hosseini-Chegeni, et al., Maternal exposure to silver nanoparticles are associated with behavioral abnormalities in adulthood: Role of mitochondria and innate immunity in developmental toxicity, Neurotoxicology, 2018, 66, 66–77.
124. N. Yin, Y. Zhang, Z. Yun, Q. Liu, G. Qu and Q. Zhou, et al., Silver nanoparticle exposure induces rat motor dysfunction through decrease in expression of calcium channel protein in cerebellum, Toxicol. Lett., 2015, 237(2), 112–120.
125. P. Su, J. Zhang, D. Wang, F. Zhao, Z. Cao and M. Aschner, et al., The role of autophagy in modulation of neuroinflammation in microglia, Neuroscience, 2016, 319, 155–167.
126. M. Shang, X. Chang, S. Niu, J. Li, W. Zhang and T. Wu, et al., The Key Role of Autophagy in Silver Nanoparticle-Induced BV2 Cells Inflammation and Polarization, Food Chem. Toxicol., 2021, 112324.
127. M. Shang, S. Niu, X. Chang, J. Li, W. Zhang and M. Guo, et al., Silver nanoparticle-induced impaired autophagic flux and lysosomal dysfunction contribute to the microglia inflammation polarization, Food Chem. Toxicol., 2022, 170, 113469.
128. L. A. Welikovitch, C. S. Do, Z. Maglóczky, J. C. Malcolm, J. Lőke and W. L. Klein, et al., Early intraneuronal amyloid triggers neuron-derived inflammatory signaling in APP transgenic rats and human brain, Proc. Natl. Acad. Sci. U. S. A., 2020, 117(12), 6844–6854.
129. K. Sikorska, I. Grądzka, B. Sochanowicz, A. Presz, S. Męczyńska-Wielgosz and K. Brzóska, et al., Diminished amyloid-β uptake by mouse microglia upon treatment with quantum dots, silver or cerium oxide nanoparticles: Nanoparticles and amyloid-β uptake by microglia, Hum. Exp. Toxicol., 2020, 39(2), 147–158.
130. S. Katarzyna, G. Iwona and W. Iwona, The Effect of Silver Nanoparticles on the Scavenger Receptor-Scara1 on Microglia, Proceedings of the 2nd World Congress on Recent Advances in Nanotechnology (RAN’17), 2017, pp. 2371–5308,  DOI:10.11159/icnb17.115.
131. K. Sikorska, I. Grądzka, I. Wasyk, K. Brzóska, T. M. Stępkowski and M. Czerwińska, et al., The impact of ag nanoparticles and cdte quantum dots on expression and function of receptors involved in amyloid-β uptake by bv-2 microglial cells, Materials, 2020, 13(14), 3227.
132. Z. Lyu, S. Ghoshdastidar, K. R. Rekha, D. Suresh, J. Mao and N. Bivens, et al., Developmental exposure to silver nanoparticles leads to long term gut dysbiosis and neurobehavioral alterations, Sci. Rep., 2021, 11(1), 6558.
133. D. A. Gonzalez-Carter, B. F. Leo, P. Ruenraroengsak, S. Chen, A. E. Goode and I. G. Theodorou, et al., Silver nanoparticles reduce brain inflammation and related neurotoxicity through induction of H2S-synthesizing enzymes, Sci. Rep., 2017, 7(1), 42871.
134. A. Sharma, V. Jaiswal, M. Park and H.-J. Lee, Biogenic silver NPs alleviate LPS-induced neuroinflammation in a human fetal brain-derived cell line: Molecular switch to the M2 phenotype, modulation of TLR4/MyD88 and Nrf2/HO-1 signaling pathways, and molecular docking analysis, Biomater. Adv., 2023, 148, 213363.
135. I. Khan, K. Saeed and I. Khan, Nanoparticles: Properties, applications and toxicities, Arabian J. Chem., 2019, 12(7), 908–931.
136. E. M. Luther, C. Petters, F. Bulcke, A. Kaltz, K. Thiel and U. Bickmeyer, et al., Endocytotic uptake of iron oxide nanoparticles by cultured brain microglial cells, Acta Biomater., 2013, 9(9), 8454–8465.
137. H.-Y. Wu, M.-C. Chung, C.-C. Wang, C.-H. Huang, H.-J. Liang and T.-R. Jan, Iron oxide nanoparticles suppress the production of IL-1beta via the secretory lysosomal pathway in murine microglial cells, Part. Fibre Toxicol., 2013, 10(1), 1–11.
138. M. Glat, H. Skaat, N. Menkes-Caspi, S. Margel and E. A. Stern, Age-dependent effects of microglial inhibition in vivo on Alzheimer's disease neuropathology using bioactive-conjugated iron oxide nanoparticles, J. Nanobiotechnol., 2013, 11(1), 1–12.
139. Y. Wang, B. Wang, M.-T. Zhu, M. Li, H.-J. Wang and M. Wang, et al., Microglial activation, recruitment and phagocytosis as linked phenomena in ferric oxide nanoparticle exposure, Toxicol. Lett., 2011, 205(1), 26–37.
140. C. Petters and R. Dringen, Uptake, metabolism and toxicity of iron oxide nanoparticles in cultured microglia, astrocytes and neurons, Springerplus, 2015, 4(Suppl 1), L32.
141. B. A. Maher, I. A. Ahmed, V. Karloukovski, D. A. MacLaren, P. G. Foulds and D. Allsop, et al., Magnetite pollution nanoparticles in the human brain, Proc. Natl. Acad. Sci. U. S. A., 2016, 113(39), 10797–10801.
142. J. Li, J. Wang, Y.-L. Wang, Z. Luo, C. Zheng and G. Yu, et al., NOX2 activation contributes to cobalt nanoparticles-induced inflammatory responses and Tau phosphorylation in mice and microglia, Ecotoxicol. Environ. Saf., 2021, 225, 112725.
143. F. Zheng, Z. Luo, C. Zheng, J. Li, J. Zeng and H. Yang, et al., Comparison of the neurotoxicity associated with cobalt nanoparticles and cobalt chloride in Wistar rats, Toxicol. Appl. Pharmacol., 2019, 369, 90–99.
144. I.-L. Hsiao and Y.-J. Huang, Effects of various physicochemical characteristics on the toxicities of ZnO and TiO₂ nanoparticles toward human lung epithelial cells, Sci. Total Environ., 2011, 409(7), 1219–1228.
145. O. Bondarenko, K. Juganson, A. Ivask, K. Kasemets, M. Mortimer and A. Kahru, Toxicity of Ag, CuO and ZnO nanoparticles to selected environmentally relevant test organisms and mammalian cells in vitro: a critical review, Arch. Toxicol., 2013, 87(7), 1181–1200.
146. A. K. Sharma, V. Singh, R. Gera, M. P. Purohit and D. Ghosh, Zinc oxide nanoparticle induces microglial death by NADPH-oxidase-independent reactive oxygen species as well as energy depletion, Mol. Neurobiol., 2017, 54(8), 6273–6286.
147. R. Dutta, B. P. Nenavathu, M. K. Gangishetty and A. Reddy, Studies on antibacterial activity of ZnO nanoparticles by ROS induced lipid peroxidation, Colloids Surf., B, 2012, 94, 143–150.
148. T. C. Long, J. Tajuba, P. Sama, N. Saleh, C. Swartz and J. Parker, et al., Nanosize titanium dioxide stimulates reactive oxygen species in brain microglia and damages neurons in vitro, Environ. Health Perspect., 2007, 115(11), 1631–1637.
149. J. Choi, Q. Zheng, H. E. Katz and T. R. Guilarte, Silica-based nanoparticle uptake and cellular response by primary microglia, Environ. Health Perspect., 2010, 118(5), 589–595.
150. L. Wei, J. Wang, A. Chen, J. Liu, X. Feng and L. Shao, Involvement of PINK1/parkin-mediated mitophagy in ZnO nanoparticle-induced toxicity in BV-2 cells, Int. J. Nanomed., 2017, 12, 1891.
151. S. Sruthi, T. Nury, N. Millot and G. Lizard, Evidence of a non-apoptotic mode of cell death in microglial BV-2 cells exposed to different concentrations of zinc oxide nanoparticles, Environ. Sci. Pollut. Res., 2021, 28(10), 12500–12520.
152. H. Liang, A. Chen, X. Lai, J. Liu, J. Wu and Y. Kang, et al., Neuroinflammation is induced by tongue-instilled ZnO nanoparticles via the Ca²⁺-dependent NF-κB and MAPK pathways, Part. Fibre Toxicol., 2018, 15(1), 1–21.
153. J. Liu, Y. Kang, W. Zheng, B. Song, L. Wei and L. Chen, et al., From the cover: ion-shedding zinc oxide nanoparticles induce microglial BV2 cell proliferation via the ERK and Akt signaling pathways, Toxicol. Sci., 2017, 156(1), 167–178.
154. H.-C. Chuang, Y.-T. Yang, H.-C. Chen, Y.-H. Hwang, K.-Y. Wu and T.-F. Chen, et al., Acute effects of pulmonary exposure to zinc oxide nanoparticles on the brain in vivo, Aerosol Air Qual. Res., 2020, 20(7), 1651–1664.
155. E. M. Moustafa, F. S. Moawed and D. F. Elmaghraby, Luteolin/ZnO nanoparticles attenuate neuroinflammation associated with diabetes via regulating MicroRNA-124 by targeting C/EBPA, Environ. Toxicol., 2023, 2691–2704.
156. D. Ziental, B. Czarczynska-Goslinska, D. T. Mlynarczyk, A. Glowacka-Sobotta, B. Stanisz and T. Goslinski, et al., Titanium dioxide nanoparticles: prospects and applications in medicine, Nanomaterials, 2020, 10(2), 387.
157. N. Rihane, T. Nury, I. M’rad, L. El Mir, M. Sakly and S. Amara, et al., Microglial cells (BV-2) internalize titanium dioxide (TiO₂) nanoparticles: toxicity and cellular responses, Environ. Sci. Pollut. Res., 2016, 23(10), 9690–9699.
158. L. Sheng, Y. Ze, L. Wang, X. Yu, J. Hong and X. Zhao, et al., Mechanisms of TiO₂ nanoparticle-induced neuronal apoptosis in rat primary cultured hippocampal neurons, J. Biomed. Mater. Res., Part A, 2015, 103(3), 1141–1149.
159. T. C. Long, N. Saleh, R. D. Tilton, G. V. Lowry and B. Veronesi, Titanium dioxide (P25) produces reactive oxygen species in immortalized brain microglia (BV2): implications for nanoparticle neurotoxicity, Environ. Sci. Technol., 2006, 40(14), 4346–4352.
160. J. A. Shin, E. J. Lee, S. M. Seo, H. S. Kim, J. L. Kang and E. M. Park, Nanosized titanium dioxide enhanced inflammatory responses in the septic brain of mouse, Neuroscience, 2010, 165(2), 445–454.
161. I.-L. Hsiao, C.-C. Chang, C.-Y. Wu, Y.-K. Hsieh, C.-Y. Chuang and C.-F. Wang, et al., Indirect effects of TiO₂ nanoparticle on neuron-glial cell interactions, Chem.-Biol. Interact., 2016, 254, 34–44.
162. Y. Xue, J. Wu and J. Sun, Four types of inorganic nanoparticles stimulate the inflammatory reaction in brain microglia and damage neurons in vitro, Toxicol. Lett., 2012, 214(2), 91–98.
163. M. E. Vance, T. Kuiken, E. P. Vejerano, S. P. McGinnis, Jr M. F. Hochella and D. Rejeski, et al., Nanotechnology in the real world: Redeveloping the nanomaterial consumer products inventory, Beilstein J. Nanotechnol., 2015, 6(1), 1769–1780.
164. D. Liu, B. Lin, W. Shao, Z. Zhu, T. Ji and C. Yang, In vitro and in vivo studies on the transport of PEGylated silica nanoparticles across the blood–brain barrier, ACS Appl. Mater. Interfaces, 2014, 6(3), 2131–2136.
165. A. D. Ducray, A. Stojiljkovic, A. Möller, M. H. Stoffel, H.-R. Widmer and M. Frenz, et al., Uptake of silica nanoparticles in the brain and effects on neuronal differentiation using different in vitro models, Nanomed. Nanotechnol. Biol. Med., 2017, 13(3), 1195–1204.
166. R. You, Y.-S. Ho, C. H.-L. Hung, Y. Liu, C.-X. Huang and H.-N. Chan, et al., Silica nanoparticles induce neurodegeneration-like changes in behavior, neuropathology, and affect synapse through MAPK activation, Part. Fibre Toxicol., 2018, 15(1), 1–18.
167. M. Delaval, S. Boland, B. Solhonne, M.-A. Nicola, S. Mornet and A. Baeza-Squiban, et al., Acute exposure to silica nanoparticles enhances mortality and increases lung permeability in a mouse model of Pseudomonas aeruginosa pneumonia, Part. Fibre Toxicol., 2015, 12(1), 1–13.
168. V. Marzaioli, J. A. Aguilar-Pimentel, I. Weichenmeier, G. Luxenhofer, M. Wiemann and R. Landsiedel, et al., Surface modifications of silica nanoparticles are crucial for their inert versus proinflammatory and immunomodulatory properties, Int. J. Nanomed., 2014, 2815–2832.
169. T. H. Shin, D. Y. Lee, B. Manavalan, S. Basith, Y.-C. Na and C. Yoon, et al., Silica-coated magnetic nanoparticles activate microglia and induce neurotoxic d-serine secretion, Part. Fibre Toxicol., 2021, 18(1), 1–18.
170. S. Hou, C. Li, Y. Wang, J. Sun, Y. Guo and X. Ning, et al., Silica Nanoparticles Cause Activation of NLRP3 Inflammasome in-vitro Model-Using Microglia, Int. J. Nanomed., 2022, 5247–5264.
171. T. H. Shin, B. Manavalan, D. Y. Lee, S. Basith, C. Seo and M. J. Paik, et al., Silica-coated magnetic-nanoparticle-induced cytotoxicity is reduced in microglia by glutathione and citrate identified using integrated omics, Part. Fibre Toxicol., 2021, 18, 1–24.
172. Z. Lyu, S. Ghoshdastidar, K. R. Rekha, D. Suresh, J. Mao and N. Bivens, et al., Developmental exposure to silver nanoparticles leads to long term gut dysbiosis and neurobehavioral alterations, Sci. Rep., 2021, 11(1), 1–14.
173. X. Li, S. Xu, Z. Zhang and H. J. Schluesener, Apoptosis induced by titanium dioxide nanoparticles in cultured murine microglia N9 cells, Chin. Sci. Bull., 2009, 54(20), 3830–3836.
174. I. L. Hsiao, C.-C. Chang, C.-Y. Wu, Y.-K. Hsieh, C.-Y. Chuang and C.-F. Wang, et al., Indirect effects of TiO₂ nanoparticle on neuron-glial cell interactions, Chem.-Biol. Interact., 2016, 254, 34–44.

---

Footnotes

† Should be considered joint author.

‡ Current affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA Phone (Fax): +982833790620-59 (cell).

---