Nanomaterials are substances that have at least one dimension between 1 and 100 nm in the three-dimensional scale, which are similar in size to DNA, proteins, and viruses. Nanomaterials are widely used in major fields due to their unique properties such as small size effect, surface effect, interface effect, and quantum effect [1,2]. Metal and metal oxide nanoparticles represent a crucial category within the family of nanomaterials. In recent years, with the rapid development of nanotechnology and material science, a variety of artificially synthesized metal and metal oxide nanoparticles, such as silver nanoparticles (Ag NPs), gold nanoparticles (Au NPs), zinc oxide nanoparticles (ZnO NPs), titanium dioxide nanoparticles (TiO2 NPs), etc., have been widely used in cell labeling sorting, biomedicine, biosensors, pharmaceuticals, etc. [[3], [4], [5]]. Their nanoscale endows them with a series of unique physicochemical properties that differ markedly from those of macroscopic bulk materials and molecular substances. Small size effects and enormous specific surface area result in an extremely high proportion of surface atoms, significantly enhancing their surface reactivity and catalytic performance [6]. Quantum size effects enable tunable transformations in optical, electrical, and magnetic properties—such as the size-dependent color change in Au NPs and the superparamagnetism in iron oxide nanoparticles (Fe2O3 NPs) [7,8]. Additionally, metal and metal oxide nanoparticles exhibit quantum tunnelling effects [9]. Compared to carbon-based nanomaterials or polymer nanoparticles, metal and metal oxide nanoparticles offer advantages in material diversity, highly tunable physicochemical properties (including optical, magnetic, and catalytic properties), and relatively mature chemical synthesis and surface functionalization strategies. However, this high reactivity also serves as the root cause of their potential biotoxicity, particularly within the complex microenvironments of biological systems [10,11]. Therefore, their biosafety, especially the risk of neurotoxicity, has become an important concern for safety evaluation and regulation.

With the increasing production, use, and release of metal and metal oxide nanoparticles, human exposure to these substances through environmental, occupational, and consumer products has risen sharply. Studies have confirmed that metal and metal oxide nanoparticles can enter the human body through the respiratory tract, the digestive tract and the skin, and deposit in the target organs after lymphatic and blood circulation and then penetrate the cell membrane and enter the mitochondria to produce cytotoxicity [12,13]. The central nervous system (CNS), one of the body's most vital yet vulnerable systems, is particularly sensitive to nanoparticle toxicity due to its active cellular metabolism, limited repair capacity, and high lipid content susceptible to oxidative assault. A growing body of in vivo and in vitro research evidence indicates that various metal and metal oxide nanoparticles can be transported across the blood-brain barrier (BBB), the olfactory nerve, and the sensory nerve endings to the CNS and accumulate in neurons and glial cells, which can cause a certain degree of neurotoxicity, resulting in damage to nerve tissues [14,15]. At present, some progress has been made on the neurotoxicity of metal and metal oxide nanoparticles. Many in vivo and in vitro studies have explored the interactions of metal and metal oxide nanoparticles with biological macromolecules, cells, organs, and tissues, and have found that the biotoxicity of metal and metal oxide nanoparticles may be caused by the mechanisms of oxidative stress, inflammatory response, cellular autophagy, and genotoxicity [[16], [17], [18]].

To address the need for knowledge integration in this field, several reviews have summarized the neurotoxic phenomena of specific metal and metal oxide nanoparticles (such as Ag NPs and TiO2 NPs) or summarized the neurotoxic pathways of nanomaterials from a general mechanism perspective [19,20]. However, with advancing research and methodological progress, existing reviews still exhibit significant gaps in comprehensiveness, depth of mechanism analysis, and theoretical framework development. Current reviews on the neurotoxicity of metal and metal oxide nanoparticles exhibit two primary limitations. First, while most reviews provide detailed accounts of molecular pathways such as oxidative stress and inflammatory responses, they fail to systematically deconstruct the synergistic or antagonistic relationship between particulate effects and ionic effects. Second, existing evaluation frameworks often categorize discussions by organ systems (BBB, neurons, glial cells) but lack standardized metrics for cross-metal comparisons.

In order to better understand the toxicity of metal and metal oxide nanoparticles to the nervous system and to further improve the biosafety assessment system, this paper reviews the pathways of metal and metal oxide nanoparticles into the nervous system, the neurotoxic effects, and the possible mechanisms of neurotoxicity, which will provide a reference for the safety evaluation and neurotoxicity investigation of nanomaterials. The primary objective of this review is to systematically elucidate and critically compare the key molecular and cellular mechanisms by which different types of metal and metal oxide nanoparticles induce neurotoxicity, while also revealing the intrinsic connections and cascading effects among these mechanisms. A secondary objective is to clarify the neurotoxicity characteristics and potentially unique mechanisms that distinguish metal and metal oxide nanoparticles from other nanomaterials. It also explores how their physicochemical properties, such as size, surface modification, and ion release capacity, determine their interactions with the nervous system and the intensity of their toxicity.

The innovation of this review lies not only in compiling existing knowledge but also in providing a mechanistically interconnected perspective. It emphasizes viewing neurotoxicity as a dynamic network event triggered by nanomaterial properties and involving the interaction of multiple cellular pathways. By highlighting how the properties of metal and metal oxide nanoparticles direct specific molecular initiation events and how different toxicity pathways intertwine and amplify damage, this review establishes a theoretical foundation and decision-making basis for more accurately assessing the neurosafety risks of metal and metal oxide nanoparticles, developing scientifically grounded toxicity prediction models, and guiding the design of next-generation high-performance nanomaterials with low neurotoxicity (Fig. 1).