Nanoparticles as MRI contrast agents for improving target nuclei localization in deep brain stimulation: a systematic review

Background: Deep brain stimulation (DBS) is an established therapeutic modality for advanced movement disorders, where clinical efficacy critically depends on sub-millimetric electrode targeting accuracy. Conventional stereotactic MRI often provides suboptimal delineation of target boundaries, such as the subthalamic nucleus (STN) and internal globus pallidus (GPi), frequently necessitating complementary intraoperative electrophysiological verification. While advanced susceptibility mapping and engineered nanoparticles have emerged to enhance target visualization, the literature conflates native iron susceptibility imaging with preclinical exogenous contrast platforms. This systematic review aims to critically evaluate the diagnostic efficacy, theranostic utility, biosafety profile, and methodological quality of studies utilizing endogenous or exogenous nanoparticle-related MRI contrast systems for DBS target localization. Methods: Following PRISMA 2020 guidelines and a registered PROSPERO protocol (CRD42024606775), a systematic search was conducted across PubMed/MEDLINE, Scopus, Web of Science, and Embase up to October 2025. Predefined eligibility criteria encompassed in vivo studies investigating either endogenous iron-based susceptibility imaging or exogenous nanoparticle contrast agents for DBS target visualization or target-associated neuromodulation. Risk of bias was systematically appraised using the Joanna Briggs Institute (JBI) critical appraisal tools, utilizing predefined quantitative thresholds. Results: Nine studies met the inclusion criteria, comprising five human cross-sectional imaging investigations ( n = 78 ) and four preclinical experimental animal studies ( n ≥ 35 ). Human studies exclusively utilized native endogenous ferritin/hemosiderin iron nanoparticles; here, Quantitative Susceptibility Mapping (QSM) at 7 T demonstrated superior structural delineation of the STN compared to standard T2 sequences, yielding Dice similarity coefficients up to 0.88 and contrast-to-noise ratio improvements of 18–23%. Preclinical animal investigations evaluated exogenous engineered nanoparticles (ultrasmall superparamagnetic iron oxide [USPIO], monocrystalline iron oxide [MION], and magnetoelectric nanodiscs), which primarily served as multimodal imaging tracers or theranostic actuators enabling wireless neuromodulation, rather than standard clinical stereotactic targeting. Documented biosafety data were sparse; dose-dependent in vitro cytotoxicity was observed at high concentrations ( > 100 μ g / mL ), while longitudinal in vivo neurotoxicity and clearance profiles were underreported. Methodological quality was judged moderate to high across the included cohort. Conclusion: Native susceptibility-based imaging (particularly 7 T QSM) currently represents the validated clinical benchmark for non-contrast direct DBS targeting. Exogenous nanoparticle contrast agents remain entirely within the preclinical domain, functioning predominantly as proof-of-concept theranostic platforms. Significant translational, regulatory (GMP/FDA), pharmacokinetic, and susceptibility artifact barriers must be overcome before exogenous nanoparticles can be integrated into routine clinical DBS targeting workflows.