Tehran University of Medical Sciences Frontiers in Biomedical Technologies 2345-5837 12 4 2025 10 01 918 940 Reza Malekzadeh Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Ramin Ghasemi Shayan Tabriz University of Medical Sciences Amir Ghasemi Jangjoo Department of Radio-Oncology, Shahid Madani Hospital, Tabriz, Iran Masoumeh Khani Department of Radiology, Shahid Madani Hospital, Tabriz University of Medical Sciences, Tabriz, Iran. Shabnam Soleimani Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran Amin Pourfarshid Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Tohid Mortezazadeh Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Mikaeil Molazadeh Department of Medical Physics, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran 2025 03 05 2025 05 24 Purpose: This review aimed to comprehensively assess how various physicochemical properties of nanoparticle-based MRI contrast agents—such as size, concentration, surface coating, charge, pH-responsiveness, and surface functionalization—affect their magnetic behavior and relaxivity. Moreover, this study evaluated the synergistic effects of these parameters to provide an integrated understanding of their combined impact on imaging performance. Materials and Methods: A systematic search was conducted across PubMed, Scopus, Web of Science, and IEEE Xplore for studies published between 2015 and 2025. Search terms included combinations of “MRI contrast agents,” “nanoparticles,” “particle size,” “surface coating,” “surface charge,” “polymer type,” “relaxivity,” “drug delivery,” and “circulation time.” The search strategy used Boolean operators (AND, OR), Medical Subject Headings (MeSH), and filters for English-language, peer-reviewed, experimental articles. Inclusion criteria focused on original studies assessing how size, surface characteristics (charge, polymer, pH responsiveness), and concentration affect MRI relaxivity and imaging performance. Data were extracted and synthesized to evaluate trends, thresholds, and correlations among parameters. Results: The review identified that nanoparticle size below 20 nm significantly enhances T₁ relaxivity, while concentrations above 0.5 mg/mL often lead to signal quenching and increased cytotoxicity. Surface coatings such as PEG and silica were found to improve biocompatibility and alter magnetic response depending on thickness and binding chemistry. Notably, the synergistic effects among these parameters were highlighted, demonstrating that optimized combinations of size, concentration, and surface coating could significantly enhance magnetic behavior and relaxivity, offering a more accurate and efficient MRI performance. This review identified threshold values for key nanoparticle properties—such as size, concentration, and surface coating—that significantly influence MRI relaxivity and imaging performance, providing a clear understanding of their combined effects. Conclusion: This review highlights that optimizing the design of nanoparticle-based MRI contrast agents requires a synergistic approach, where key parameters—size, concentration, surface coating, and surface functionalization—are co-engineered to enhance magnetic behavior and relaxivity. Specifically, maintaining particle sizes below 20 nm, using biocompatible coatings like PEG or silica, and optimizing concentration between 0.1–0.5 mg/mL were identified as critical factors. This integrated framework provides a guideline for developing next-generation contrast agents with superior imaging performance and minimal toxicity. https://fbt.tums.ac.ir/index.php/fbt/article/view/1237 https://fbt.tums.ac.ir/index.php/fbt/article/download/1237/528