Traumatic brain injury (TBI) represents a significant global health burden, contributing to substantial mortality and long-term disability worldwide [1], [2]. The pathophysiology of TBI is not a single event but a dynamic and multifaceted process, which can be generally divided into primary and secondary injury phases. The primary injury is caused by the immediate mechanical forces, including acceleration, deceleration, or impact, resulting in shearing and compression of neural tissue, blood vessels, and axons. This initial insult triggers a complex and often sustained cascade of secondary injury, characterized by excitotoxicity, widespread neuroinflammation, oxidative stress, mitochondrial dysfunction, and programmed cell death [3], [4], [5]. This complicated interaction between molecules and cells can evolve over hours to days, ultimately determining the degree of neuronal loss and clinical outcome for patients [6], [7]. Therefore, the heterogeneity of TBI performance and progression, which can be influenced by the injury mechanisms, location, and individual differences, makes standardized diagnosis and treatment challenging.
The accurate diagnosis and management of TBI largely rely on neuroimaging techniques, which aims to visualize the structural and functional consequences of the injury [8], [9], [10]. Currently, computed tomography (CT) remains the first-line imaging modality in the acute condition due to its wide availability, fast scanning time, and high sensitivity for detecting life-threatening conditions such as skull fractures and hematoma lesions requiring neurosurgical intervention [11]. However, the application of CT is limited by its insufficient soft-tissue contrast and its insensitivity to non-hemorrhagic diffuse pathologies, which are major causes to long-term cognitive and functional deficits [12], [13].
Magnetic resonance imaging (MRI) has made significant progress with its superior soft-tissue resolution [14], [15]. Conventional MRI sequences (such as T1-weighted, T2-weighted, FLAIR) can identify contusions, edema, and some white matter abnormalities [16], [17], [18]. However, they often fail to detect micro-hemorrhages and the full extent of axonal injury, which can only be reliably visualized through specialized sequences such as susceptibility weighted imaging (SWI) or diffusion tensor imaging (DTI) [19], [20], [21]. Additionally, although advanced techniques like positron emission tomography (PET) can identify metabolic and neuroinflammatory processes, they involve ionizing radiation and provide limited spatial resolution, making them impractical for routine monitoring [22], [23]. These limitations collectively generate a gap between underlying pathology and reported symptoms, thereby complicating clinical diagnosis and management. Without reliable methods to visualize the full spectrum of microstructural and molecular injuries, diagnostic certainty is reduced, leading to compromised prognostic accuracy. This not only delays the timely implementation of optimal therapies, but also hinders the effective monitoring of treatment response.
The integration of nanotechnology and medicine has facilitated a paradigm shift in biomedical imaging, providing innovative solutions to long-standing diagnostic limitations. Nanomaterials, defined by their nanoscale dimensions (typically ranging from 1 to 100 nm), exhibit unique physicochemical properties that are distinct from their bulk counterparts or small molecules. These characteristics, such as a high surface-to-volume ratio, tunable core composition, and modifiable surface chemistry, make them promising multifunctional platforms for engineering advanced imaging contrast agents [24], [25]. Their structural design allows for the precise control of their optical and magnetic, and electronic properties, enabling the production of agents with dramatically enhanced brightness, relaxivity, or stability. More importantly, their surface can be functionalized with polymers (such as polyethylene glycol (PEG) for stealth nature) and a diverse array of targeting ligands (such as peptides, antibodies, aptamers) to control their pharmacokinetics, biodistribution, and specificity for biological targets. This engineering design facilitates the development of “smart” or “activatable” nanoprobes that remain silent in normal tissues but generate imaging signals after encountering a specific pathological trigger, such as an upregulated enzyme or an abnormal pH value, within the disease microenvironment [26], [27], [28], [29].
The application of these sophisticated nano-based imaging agents in TBI imaging holds potential to bridge the current diagnostic gaps [30]. Their size and surface properties enable them to passively accumulate in regions with a compromised blood-brain barrier (BBB) in TBI lesion through an enhanced permeability and retention (EPR)-like effect, similar with that observed in tumors [31], [32]. This results in significantly higher accumulation and prolonged retention at the injury site, thereby enhancing imaging contrast precisely where pathology is most acute [33]. More importantly, by conjugating ligands that target biomarkers of neuronal death, glial activation, or inflammation, these nanoprobes can actively accumulate in regions associated with specific cellular and molecular events of the secondary injury cascade [34], [35], [36]. This active targeting shifts imaging from a simply anatomical process to a functional and molecular examination, allowing for the detection of pathogenic processes before they lead to macroscopic tissue damage. In addition, the multifunctional capacity of nanomaterials allows for the construction of multi-modality nanoprobes, such as a single nanoparticle that can be detected by both fluorescence imaging and MRI, which enable cross-validation and the correlation of high-sensitivity molecular data with high-resolution anatomical information [37], [38], [39]. This capability for targeted, multiparametric assessment promises not only to reveal micro-injuries with high clarity but also to classify TBI into distinct molecular subtypes, paving the way for personalized treatment of neurotrauma.
This review provides an overview of the rapidly advancing field of nanomaterials as advanced imaging contrast agents for enhancing the diagnosis of TBI (Scheme 1). It will systematically explore the application of nanotechnology across two key imaging modalities: fluorescence imaging and MRI. For the fluorescence imaging, the discussion focuses on how nanomaterials facilitate high-sensitivity molecular profiling, enable the objective assessment of injury severity, and provide real-time guidance for surgical and medical interventions. Regarding MRI, the review highlights the role of nanomaterials both in enhancing contrast sensitivity to detect micro-lesions and in enabling multiparametric imaging for a comprehensive understanding of the injury’s pathophysiology. Finally, the review concludes with a discussion of the existing challenges related to clinical translation, while offering the future perspective of cutting-edge technology.