Stimuli-responsive contrast agents (CAs) have shown great promise in enhancing magnetic resonance imaging (MRI) for more accurate tumor diagnosis. However, current CAs still face challenges in achieving high accuracy due to their low specificity and contrast signals being confounded by potential endogenous MRI artifacts. Herein, an extremely small iron oxide nanoparticle (ESIONP)-based smart responsive MRI contrast agent (LESPH) is proposed, which is meticulously designed with sequential dual biochemical stimuli-initiated, time-resolved T1 and T2 contrast presentation, ensuring high tumor specificity while minimizing interference from endogenous artifacts. LESPH is constructed using emulsion solvent evaporation by assembling poly(2-(hexamethyleneimino) ethyl methacrylate) terminally conjugated with a disulfide bond-linked catechol group (DSPH)-modified ESIONPs, with lauryl betaine serving as a surfactant. When LESPH undergoes sequential responses to the weak acidity and high-concentration glutathione (GSH) in the tumor microenvironment, it experiences an extremely rapid transition from sparse ESIONP assemblies to dispersed ESIONPs, followed by a slower transition to closely aggregated ones, concomitantly providing distinguishable brightening and darkening contrast enhancement at the tumor location on different time scales. By virtue of its sequential dual responsiveness and time-resolved distinguishable contrast enhancements, LESPH successfully detects tumors with extremely high accuracy, providing a novel paradigm for the precise medical diagnosis of cancer.

Vegetable oils such as oleic acid have been widely used in the synthesis of nanomaterials as they are environmentally benign, cheap, and biodegradable. Ricinoleic acid (RA), which differs from oleic acid by the presence of an additional hydroxyl group, has surprisingly remained unexplored in the preparation of metal oxide nanoparticles, although it offers the advantage over oleic acid of easy functionalization due to the presence of the hydroxyl group. Here is a simple one-pot procedure for the synthesis of a variety of superparamagnetic nanoparticles, iron oxides and ferrites, using RA both as a precursor complexing agent and as a capping agent outlined. This procedure overcomes the challenges associated with the traditional thermal decomposition method, which demands separate precursor preparation and purification steps, thus promoting a simple yet scalable economic production of various magnetic nanoparticles. Minor changes in the reaction conditions allowed for the production of nanoparticles with different sizes, ranging from 5 to 17 nm, as well as different shapes, spherical and cuboid. Iron oxide nanospheres with an average particle size of 10 nm were superparamagnetic at room temperature with a saturation magnetization of 41 emu g-1. The as-prepared RA-coated nanoparticles are hydrophobic and dispersible in non-polar solvents but may easily be rendered hydrophilic and water dispersible; epoxidation, followed by alkaline ring-opening, produced hydroxylated nanoparticles with a positive zeta potential of 31 eV, whereas exchange of the capping RA with nitrilotriacetic acid (NTA) gave nanoparticles with a negative zeta potential of -25 eV. The present study highlights the uniqueness of using RA in the preparation of magnetic nanoparticles; apart from the ease and economics of scaling, it offers the possibility of the nanoparticles being either hydrophobic or hydrophilic.

The continuous discovery of novel effective antibacterial agents using nano-based materials is of high significance. In this study, we utilized Polymerylated divalent-metal-doped ferrite nanoparticles (PMFe2O4 NPs) and studied their antibacterial inhibition effects. Different panels of PVP- and PEG-coated metal-doped MFe2O4 (M ≅ Co, Ni, and Zn) were prepared via the Ko-precipitation Hydrolytic Basic (KHB) methodology and thoroughly analyzed using TEM, XRD, FTIR, and VSM. The as-synthesized doped ferrites displayed stable quasi-spherical particles (7-15 nm in size), well-ordered crystalline cubic spinel phases, and high-saturation magnetizations reaching up to 68 emu/g. The antibacterial efficacy of the doped ferrites was then assessed against a Gram-negative E. coli bacterial strain. The results demonstrated that both metal doping and polymer functionalization influence the antimicrobial efficacies and performance of the ferrite NPs. The presence of the PVP polymer along with the divalent metal ions, particularly Co and Ni, resulted in the highest antibacterial inhibition and effective inactivation of the bacterial cells. The antibacterial performance was as follows: PVP-CoFe2O4 > PVP-NiFe2O4 > PVP-ZnFe2O4. Lastly, cell viability assays conducted on human breast fibroblast (HBF) cells confirmed the good safety profiles of the doped ferrites. These interesting results demonstrate the distinctive inhibitory features of the biocompatible metal-doped ferrites in enhancing bacterial killing and highlights their promising potential as effective antimicrobial agents, with possible applications in areas such as water disinfection, biomedical devices, and antimicrobial coatings.

Chemodynamic therapy (CDT), which utilizes the catalytic reactions of nanoparticles to inhibit tumor growth, is a promising approach in cancer therapy. However, its efficacy is limited by insufficient hydrogen peroxide (H2O2) concentration in tumor microenvironments and unsatisfactory enzymatic catalytic activity. To overcome these limitations, ultra-small iron-based (USIB) nanoparticles with cascaded superoxide dismutase (SOD)-mimic and peroxidase (POD)-mimic activities have been engineered. USIB nanoparticles initiated by SOD-mimic activity to transform superoxide anions (O2·-) into H2O2, elevating H2O2 levels in the tumor microenvironment and subsequently utilizing POD-mimic activity to convert H2O2 into the more reactive ·OH, thereby achieving the destruction of tumor cells. In addition, USIB nanoparticles possess photothermal conversion capabilities, and their enzymatic activity can be significantly enhanced under mild laser irradiation. Therefore, by addressing the issues of insufficient substrate concentration and low enzymatic catalytic activity, the therapeutic efficiency of CDT has been improved. Our research integrates the cascade catalytic reactions of nanozymes with laser irradiation, effectively inhibiting tumor growth and exhibiting outstanding biosafety, demonstrating promising therapeutic potential.

Glutathione serves as a common biomarkers in tumor diagnosis and treatment. The levels of its intracellular concentration permit detailed investigation of the tumor microenvironment. However, low polarization and weak Raman scattering cross-section make direct and indirect Raman detection challenging. This study designs an amorphous-crystalline urchin-like TiO2 (AC-UL-TiO2) for the accurate identification of GSH and GSSG. By synergistically regulating the crystalline core and amorphous shell, the bandgap structure is optimized, thereby enhancing charge transfer efficiency. AC-UL-TiO2 demonstrates excellent SERS performance in detecting dye molecules with good selectivity for mixed analytes. The enhancement factor (EF) for R6G is 6.89 × 106, and the limit of detection (LOD) is 10-10 M. A SERS-colorimetric dual-modality platform is developed based on the AC-UL-TiO2@DTNB system to accurately monitor GSH concentrations from 0 to 1000 µM, providing a robust dual-confirmation result. Importantly, combined with the principal component analysis method, the AC-UL-TiO2 SERS platform can directly distinguish GSH and GSSG molecules. Besides, direct SERS detection LOD for GSH and GSSG are 10-8 M, which is 100 times higher than that of indirect detection. These findings indicate that AC-UL-TiO2 holds potential for biomarkers trace detection in tumor microenvironments.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a crucial tool for the diagnosis and management of various diseases globally. Iron oxide nanoparticles with sizes less than 5 nm are expected to address the long-term toxicity and brain accumulation issues associated with clinical gadolinium-based T1 contrast agents (GBCAs) due to their non-toxicity and biodegradability. However, synthesizing sub-5-nanometer particles presents significant challenges that complicate their clinical translation. Herein, traditional iron oxide-based negative (T2) agents into positive (T1) agents are transformed and an all-in-one multielement doping strategy is developed. Multiple elements into iron oxide crystals are introduced to form multielement doping engineered iron oxide nanoparticles (MDE-IONPs) and their surfaces with flexible hydrophilic ligands are subsequently modified. It is shown that Ni (II) and Gd (III) doping engineered nanoparticles can effectively enhance imaging efficacy, reducing clearance rates, and enabling controlled synthesis. Ultimately, the implementation of Ni (II) and Gd (III) co-engineering yield longitudinal relaxivity of up to 14.7 mM-1s-1 even for particles as large as 9 nm, an improvement of approximately 300% over GBCAs. Combined with the stability, biosafety, both in vitro and in vivo results suggest that all-in-one multielement doping is a favorable strategy for advancing the development of next-generation safe MRI contrast agents.

Iron oxide nanoparticles are a promising candidate for the dual-mode MRI contrast agent, however most of them have limited circulation time and predominant negative contrast. We developed citric acid stabilized superparamagnetic maghemite nanoparticles (CA-SPMNs) with size 3.2 ± 0.7 nm with intense positive contrast. Co-precipitation reactions under well-controlled conditions in the automatic chemical reactor have carried out the synthesis. We found an encouraging correlation between aggregate formation kinetics in biological media and in vitro cytotoxicity results and in vivo circulation time. A cytotoxicity test showed the mouse fibroblast viability over 80 % for iron doses exceeding 1 mg/mL. CA-SPMNs have a low r2/r1 ratio, exhibiting positive contrast. Using in vivo MRI we demonstrated that CA-SPMNs circulate in the blood for 12-24 h, enabling blood vessel and tumor visualization, and partial renal clearance. Finally, CA-SPMNs show promise as effective MRI contrast agents, enabling differentiation between normal and pathological tissues.

This study presents a novel synthesis method for fabricating magnetic-plasmonic Fe3O4@CS-AuNPs nanocomposite utilizing aryldiazonium gold(III) salts. The low reduction potential of aryldiazonium gold salts enables their spontaneous reduction on the surface of Fe3O4 NPs stabilized with chitosan (CS), as CS facilitates the electron transfer process. The Fe3O4@CS-AuNPs nanocomposite exhibited gold plasmon peaks at 525 nm in UV-vis spectra and demonstrated long shelf life in an aqueous solution, with a ζ-potential of -42.8 mV. XPS revealed the complete reduction of gold(III) supported by the Au 4f peak for Fe3O4@CS-AuNPs. The increased Fe(II) ratio in XPS suggests a green reduction, where chitosan reduced Au(III) to Au(0). HR-TEM images demonstrated that Fe3O4@CS-AuNPs have an average nanoparticle size of 17.0 ± 3.8 nm. The high surface area of 55.15 m2/g for Fe3O4@CS-AuNPs supports their enhanced adsorption and removal of E. coli bacteria. Fe3O4@CS-AuNPs exhibited superior removal efficiencies of 100%, 99%, and 97%, outperforming Fe3O4@CS bacteria removal of 3%, 21%, and 40%. Surface modification with arylated AuNPs enhanced the adsorption and bacterial binding, enabling Fe3O4@CS-AuNPs to demonstrate high capture efficiency and bactericidal activity, eliminating viable bacteria at a minimum inhibitory concentration (MIC) of 50%. These findings highlight the potential of Fe3O4@CS-AuNPs for enhanced microbial removal.

Castration-resistant prostate cancer (CRPC) is an intractable disease, but approaches for eradicating primary tumors and inhibiting metastasis are limited. Considering that lipid metabolism plays key roles in ferroptosis and tumor progression and treatment resistance, here we developed a biomimetic nanovesicle (FiFe@RBM) encapsulating fatty acid synthetase inhibitors and iron oxide nanoparticles for synergistic therapy of CRPC and inhibiting the metastasis. FiFe@RBM with superior magnetic properties efficiently delivered drugs into the CRPC cancer cells, where it can release Fe ions to efficiently induce reactive oxygen species and mitochondrial dysfunction and inhibit the AKT-mTOR pathway, which synergistically causes apoptosis and enhances ferroptosis by rewired lipid metabolism through increasing polyunsaturated fatty acids (PUFAs), PUFA-enriched phosphatidylcholine (PUFA-PC), PUFA-enriched phosphatidylethanolamine (PUFA-PE), etc. By intravenous injection, the high accumulation of FiFe@RBM in PC-3 tumors enabled precision T1/T2-weighted magnetic resonance imaging-guided effective eradication of human CRPC PC-3 tumors by synergistic magnetic hyperthermia therapy (MHT) and ferroptosis, which further inhibited liver metastasis by the activated and recruited high rates of natural killer cells in the nude mice model. This work presents an effective nanovesicle strategy for reprogramming lipid metabolism to enhance ferroptosis in synergy with MHT for effectively treating refractory cancers.

Individual theranostics with an integrated multifunction holds considerable promise for clinical application compared with multicomponent regimes. Mn3O4 nanoparticles with an ultrasmall size (4 nm) and mass production capability were developed with dual function of integrated tumor magnetic resonance imaging (MRI) and therapy. The high valence state of Mn3O4 nanocrystals enables a sensitive reaction with the glutathione (GSH) molecule and favorable decomposition ability, which further induces a unique, favorable, variable T 1 turn-off and T 2 turn-on MRI property. In addition, ultrasmall Mn3O4 nanoparticles reacted with high-level GSH in the tumor microenvironment induces responsive and enhanced variable T 1- and T 2-MRI imaging capability for accurate cancer diagnosis. Moreover, the synthesized ultrasmall Mn3O4 nanoparticles exhibit considerable ferroptosis effect towards tumor cells and excellent in vivo biocompatibility, thus indicating promising effective cancer treatment application. The developed ultrasmall Mn3O4 nanoparticles with integrated dual functions of GSH-responsive variable T 1 and T 2 MRI imaging effects and ferroptosis capability show promising potential as a candidate for tumor theranostics in clinical applications.

The emergence of nanomedicine offers renewed promise in the diagnosis and treatment of diseases. Due to their unique physical and chemical properties, iron oxide nanoparticles (IONPs) exhibit widespread application in the diagnosis and treatment of various ailments, particularly tumors. IONPs have magnetic resonance (MR) T1/T2 imaging capabilities due to their different sizes. In addition, IONPs also have biocatalytic activity (nanozymes) and magnetocaloric effects. They are widely used in chemodynamic therapy (CDT), magnetic hyperthermia treatment (MHT), photodynamic therapy (PDT), and drug delivery. This review outlines the synthesis, modification, and biomedical applications of IONPs, emphasizing their role in enhancing diagnostic imaging (including single-mode and multimodal imaging) and their potential in cancer therapies (including chemotherapy, radiotherapy, CDT, and PDT). Furthermore, we briefly explore the challenges in the clinical application of IONPs, such as surface modification and protein adsorption, and put forward opinions on the clinical transformation of IONPs.

Magnetic resonance imaging (MRI) is a noninvasive and radiation-free technique used for soft tissue. However, there are some limitations of the MRI modality, such as low sensitivity and poor image resolution. Artificially engineered magnetic nanoprobes have been extensively explored as a versatile platform for ultrasensitive MRI contrast agents due to their unique physiochemical characteristics and tunable magnetic properties. In this review, the emphasis is on recent progress in MRI nanoprobes with different structures and elements, including gadolinium-, iron-, manganese-based and metal-free nanoprobes. The key influencing factors and advanced engineering strategies for modulating the relaxation ratio of MRI nanoprobes are systematically condensed. Furthermore, the widespread and noninvasive visualization applications of MRI nanoprobes for real time monitoring of major organs and accurate disease diagnosing, such as cerebrovascular, ischemia, Alzheimer's disease, liver fibrosis, whole-body tumors, inflammation, as well as multi-mode imaging applications are summarized. Finally, the challenges and prospects for the future development of MRI nanoprobes are discussed, and promising strategies are specifically emphasized for improving biocompatibility, precisely engineering of optimal size, AI-driven prediction and design, and multifunctional self-assembly to enhance diagnostics. This review will provide new inspiration for artificial engineering and nanotechnology-based molecular probes for medical diagnosis and therapy with ultrasensitive MRI.

Magnetic nanoparticles (MNPs) are produced for both diagnosis and treatment due to their simultaneous availability in magnetic resonance imaging (MRI) and magnetic hyperthermia (MHT). Extensive investigations focus on developing MNPs for individual MHT or MRI applications, but the development of MNPs for theragnostic applications has received very little attention. In this study, through efficient examination of synthesis conditions such as metal precursors, reaction parameters, and solvent choices, we aimed to optimize MNP production for effective utilization for MHT and MRI simultaneously. MNPs were synthesized by thermal decomposition under 17 different conditions and deeply characterized by transmission electron microscopy (TEM), x-ray diffraction (XRD), and x-ray photoelectron spectroscopy (XPS). The heating efficiency of MNPs under an alternating current (AC) magnetic field was quantified, while MRI performance was evaluated through agar phantom experiments. Our findings highlight the crucial role of benzyl ether in metal ion reduction and size control. Metal-doped iron oxide MNPs displayed promise for MHT, whereas Mn-doped iron oxide MNPs exhibited enhanced MRI capabilities. Consequently, five engineered MNPs were considered potential candidates for further studies, demonstrating their dual ability in MRI and MHT.

Nitric oxide (NO), a pivotal signalling molecule, plays multifaceted roles in physiological and pathological processes, including cardiovascular and immune functions, neurotransmission and cancer progression. Nevertheless, measuring NO in vivo is challenging due to its transient nature and the complexity of the biological environment. Here we describe NO-responsive magnetic probes made of crosslinked superparamagnetic iron oxide nanoparticles tethered to a NO-sensitive cleavable linker for highly sensitive and selective NO magnetic resonance imaging in vivo. These probes enable the detection of NO at concentrations as low as 0.147 μM, allowing for the imaging and quantification of NO in mouse tumour models, studying its effects on tumour progression and immunity and assessing the response of tumour-associated macrophages to cancer immunotherapeutic agents. Additionally, they facilitate concurrent anatomical and molecular imaging of organs, helping to identify pathological alterations in the liver. Overall, these probes represent promising non-invasive tools for investigating the dose-dependent conflicting role of NO in physiological and pathophysiological processes.

Prior research has highlighted the reduction of iron oxide nanoparticle (IONPs) sizes to the "ultra-small" dimension as a pivotal approach in developing T1-MRI contrast agents, and the enhancement in T1 contrast performance with the reducing size is usually attributed to the increased specific surface area and weakened magnetization. Nonetheless, as the size decreases, the variation in surface defects, particularly oxygen vacancy (VO) defects, significantly impacts the T1 imaging efficacy. In this study, the VO on IONPs is meticulously investigated through XPS, Raman, and EPR spectroscopy. As the nanoparticle size decreased, the VO concentration rose initially but subsequently declined, with the peak concentration observed in the size of 8.27 nm. Further insights gained from synchrotron XAS analysis and DFT calculations indicate that both surface tension and phase transition in IONPs contribute to alterations in the Fe─O bond length, thereby influencing the VO formation energy across varying nanoparticle sizes. The MRI tests reveal that the VO in IONPs serve as pivotal sites for the attachment of water molecules to iron ions, and IONPs with fewer VO exhibited a deterioration in T1-MRI contrast effects. This research may provide a deeper understanding of the relationship between T1 contrast performance and the size of IONPs.

This review highlights recent progress in utilizing iron oxide nanoparticles (IONPs) as a safer alternative to gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). It consolidates findings from multiple studies, discussing current T1 contrast agents (CAs), the synthesis techniques for IONPs, the theoretical principles for designing IONP-based MRI CAs, and the key factors that impact their T1 contrast efficacy, such as nanoparticle size, morphology, surface modifications, valence states, and oxygen vacancies. Furthermore, we summarize current strategies to achieve IONP-based responsive CAs, including self-assembly/disassembly and distance adjustment. This review also evaluates the biocompatibility, organ accumulation, and clearance pathways of IONPs for clinical applications. Finally, the challenges associated with the clinical translation of IONP-based T1 CAs are included.

Vascular dysfunction, characterized by changes in anatomy, hemodynamics, and molecular expressions of vasculatures, is closely linked to the onset and development of diseases, emphasizing the importance of its detection. In clinical practice, medical imaging has been utilized as a significant tool in the assessment of vascular dysfunction, however, traditional imaging techniques still lack sufficient resolution for visualizing the complex microvascular systems. Over the past decade, with the rapid advancement of nanotechnology and the emergence of corresponding detection facilities, engineered nanomaterials offer new alternatives to traditional contrast agents. Compared with conventional small molecule counterparts, nanomaterials possess numerous advantages for vascular imaging, holding the potential to significantly advance related technologies. In this review, the latest developments in nanotechnology-assisted vascular imaging research across different imaging modalities, including contrast-enhanced magnetic resonance (MR) angiography, susceptibility-weighted imaging (SWI), and fluorescence imaging in the second near-infrared window (NIR-II) are summarized. Additionally, the advancements of preclinical and clinical studies related to these nanotechnology-enhanced vascular imaging approaches are outlined, with subsequent discussion on the current challenges and future prospects in both basic research and clinical translation.

This work presents a group of high-quality hydrophilic and negatively charged coated, iron oxide magnetic nanoparticles (MNPs) that have been prepared using a microwave-ultrasound-assisted protocol, and demonstrates the great impact that the synthetic strategy has on the resulting MNPs. The different coatings tested, including citric acid, carboxymethyl dextran and β-cyclodextrin (βCD)/citric acid have been compared and have shown good dispersibility and stability. The ability of βCD to maintain the inclusive properties of the coated MNPs has been proven as well as their cytocompatibility. An amino citrate-modified βCD is proposed and its capabilities as a flexible amphoteric adsorbing device have been studied. The NMR relaxometric properties of the coated MNPs have been investigated using field-cycling nuclear magnetic relaxation dispersion profiles. For the amino citrate-modified βCD system, the order of magnitude of the Néel relaxation time is in the typical range for superparamagnetic systems' reversal times, i.e., 10-10-10-7 s. The r d value corresponds to the physical radius of the magnetic core, suggesting that, in this particular case, the coating does not prevent the diffusive motion of water molecules, which provide the basis for potential future magnetic resonance imaging (MRI) applications.

Iron oxide nanoparticles (IONPs) have garnered significant attention in biomedical applications due to their unique magnetic properties, biocompatibility, and versatility. This review comprehensively examines the synthesis methods, surface functionalization techniques, and diverse biomedical applications of IONPs. Various chemical and physical synthesis techniques, including coprecipitation, sol-gel processes, thermal decomposition, hydrothermal synthesis, and sonochemical routes, are discussed in detail, highlighting their advantages and limitations. Surface functionalization strategies, such as ligand exchange, encapsulation, and silanization, are explored to enhance the biocompatibility and functionality of IONPs. Special emphasis is placed on the role of IONPs in biosensing technologies, where their magnetic and optical properties enable significant advancements, including in surface-enhanced Raman scattering (SERS)-based biosensors, fluorescence biosensors, and field-effect transistor (FET) biosensors. The review explores how IONPs enhance sensitivity and selectivity in detecting biomolecules, demonstrating their potential for point-of-care diagnostics. Additionally, biomedical applications such as magnetic resonance imaging (MRI), targeted drug delivery, tissue engineering, and stem cell tracking are discussed. The challenges and future perspectives in the clinical translation of IONPs are also addressed, emphasizing the need for further research to optimize their properties and ensure safety and efficacy in medical applications. This review aims to provide a comprehensive understanding of the current state and future potential of IONPs in both biosensing and broader biomedical fields.

Iron oxide nanoparticles (IONPs) have shown great promise in biomedical applications, particularly as MRI contrast agents due to their magnetic properties and biocompatibility. Although several IONPs have been approved by regulatory agencies as MRI contrast agents, their primary application as negative contrast agents limits their usage. Additionally, there is an emerging need for the development of molecular contrast agents that can specifically target biomarkers, enabling more accurate and sensitive diagnostics. To address these challenges, we exploited the engineerability of proteins to stabilize IONPs with tailored magnetic properties, creating protein-stabilized iron oxide nanoparticles (Prot-IONPs) and leveraged the chemical diversity of proteins to functionalize Prot-IONPs with targeting moieties. As a proof-of-concept, we used alendronate (Ald) to target atherosclerotic plaques in the aorta. Simple protein functionalization allowed targeting while maintaining the stability and relaxation properties of the Prot-IONPs. Prot-IONPs-Ald successfully enabled positive contrast imaging of atherosclerotic plaques in vivo in an atherosclerotic mouse model (ApoE-/- mice on a high-fat diet). This study demonstrates the potential of engineering protein-nanoparticle hybrids as versatile platforms for developing targeted in vivo MRI contrast agents.

Nanoparticle-based thin films are increasingly being used in various applications. One of the key factors that determines the properties and performances of these films is the type of ligands attached to the nanoparticle surfaces. While long-chain surfactants, such as oleic acid, are commonly employed to stabilize nanoparticles and ensure high monodispersity, these ligands often hinder charge transport due to their insulating nature. Although thermal annealing can remove the long-chain ligands, the removal process often introduces defects such as cracks and voids. In contrast, the use of short-chain organic or inorganic ligands can minimize interparticle distance, improving film conductivity, though challenges such as incomplete ligand exchange and residual barriers remain. Polymeric ligands, especially block copolymers, can also be employed to create films with tailored porosity. This review discusses the effects of various ligand types on the morphology and performance of nanoparticle-based films, highlighting the trade-offs between conductivity, structural integrity, and functionality.

The application of nanotechnology in the molecular diagnosis and treatment of cancer is essential.

This study aimed to investigate the influence of curcumin-coated ultra-small superparamagnetic iron oxide (USPIO) as a T1 contrast agent in Magnetic Resonance Imaging (MRI).

In this experimental study, the influence of curcumin-coated USPIO (Fe3O4@C) on the diagnosis of the cancer cell line was investigated. After synthesis, characterization, and relaxation of Fe3O4@C, the contrast changes in T1-weight MRI to mouse colon carcinoma 26 cell line were evaluated in vitro.

Fe3O4@C nanoparticles (NPs) are good at imaging; based on a relaxometry test, the r1 and r2 relaxivities of Dotarem were 3.139 and 0.603 mM-1s-1, respectively. Additionally, the r1 and r2 relaxivities of Fe3O4@C were 3.792 and 1.3 mM-1s-1, respectively, with the rate of 2.155 of r2/r1 NPs.

The NPs can be identified as a positive contrast agent with a weight of T1 in MRI. The coresh-ell Fe3O4@C NPs can be effective in cancer treatment and diagnosis because of the therapeutic effects of curcumin and the properties of USPIO.

The early diagnosis of hepatocellular carcinomas (HCCs) remains challenging in the clinic. Primovist-enhanced magnetic resonance imaging (MRI) aids HCC diagnosis but loses sensitivity for tumors <2 cm. Therefore, developing advanced MRI contrast agents is imperative for improving the diagnostic accuracy of HCCs in very-early-stage. To address this challenge, PEGylated ultra-small iron oxide nanoparticles (PUSIONPs) are synthesized and employed as liver-specific T1 MRI contrast agents. Intravenous delivery produces simultaneous hyperintense HCC and hypointense hepatic parenchyma signals on T1 imaging, creating an extraordinarily high tumor-to-liver contrast. Systematic studies uncover PUSIONP distribution in hepatic parenchyma, HCC lesions at the organ, tissue, cellular, and subcellular levels, revealing endosomal confinement of PUSIONP without aggregation. By mimicking such situations, the dependency of relaxometric properties on local PUSIONP concentration is investigated, emphasizing the key role of different endosomal concentrations in liver and tumor cells for high tumor-to-liver contrast and clear tumor boundaries. These findings offer exceptional imaging capabilities for early HCC diagnosis, potentially benefiting real HCC patients.

Rapid and accurate assessment of conditions characterized by altered blood flow, cardiac blood pooling, or internal bleeding is crucial for diagnosing and treating various clinical conditions. While widely used imaging modalities such as magnetic resonance imaging (MRI), computed tomography (CT), and ultrasound offer unique diagnostic advantages, they fall short for specific indications due to limited penetration depth and prolonged acquisition times. Magnetic particle imaging (MPI), an emerging tracer-based technique, holds promise for blood circulation assessments, potentially overcoming existing limitations with reduction in background signals and high temporal and spatial resolution, below the millimeter scale. Successful imaging of blood pooling and impaired flow necessitates tracers with diverse circulation half-lives optimized for MPI signal generation. Recent MPI tracers show potential in imaging cardiovascular complications, vascular perforations, ischemia, and stroke. The impressive temporal resolution and penetration depth also position MPI as an excellent modality for real-time vessel perfusion imaging via functional MPI (fMPI). This review summarizes advancements in optimized MPI tracers for imaging blood circulation and analyzes the current state of pre-clinical applications. This work discusses perspectives on standardization required to transition MPI from a research endeavor to clinical implementation and explore additional clinical indications that may benefit from the unique capabilities of MPI.

Iron oxide nanoparticles (IONPs) have garnered significant interest as magnetic resonance imaging (MRI) contrast agents due to their exceptional magnetic properties and biocompatibility. Toward more precise diagnosis of diseases, the relaxometric properties of IONPs have become a key research focus. Despite extensive studies on structural factors such as size, morphology, surface modification, crystalline phase, and aggregation state, the correlation between the intrinsic structure and relaxometric behavior remains unclear, particularly for ultrasmall IONPs. To address this issue, we carefully compared IONPs with identical size, shape, and surface modification and found out strong correlations among the content of Fe2+ ions, oxygen vacancies, and the relaxometric properties. By optimizing the reaction system, ultrasmall IONPs showing outstanding relaxometric performance, with longitudinal relaxivity up to 9.0 mM-1 s-1 and transverse relaxivity up to 28.5 mM-1 s-1, were successfully obtained. These results underscore the pivotal role of Fe2+ in the relaxometric properties of IONP-based MRI contrast agents.

The synthesis of Superparamagnetic Iron Oxide Nanoparticles (SPIONs) with size and shape tunability, which is also industrially scalable, remains challenging. Surface functionalization of the nanoparticles is yet another active research subject. Although a variety of inorganic and organometallic precursors have been tried, which are demanding in terms of both cost and effort, the use of iron hydroxide, a simple and cheap iron precursor, has not been explored in detail for the synthesis of SPIONs following a thermal decomposition route. Here, we outline a simple one-pot thermal decomposition route that avoids separate precursor preparation and purification steps and, consequently, is easily scalable. The method involves the alcoholic hydrolysis of a simple iron salt into iron hydroxide, which, on addition of oleic acid, forms the precursor oleate complex in situ, which is subsequently thermally decomposed to produce monodispersed SPIONS. Minor modifications allow for particle dimensions (5-20 nm) and morphology (spheroid or cuboid) to be controlled. Additionally, we explored a simple ligand exchange process for rendering the hydrophobic nanoparticles hydrophilic. Trisodium nitrilotriacetate (NTA), a readily available polycarboxylate, can efficiently transfer the oleate-coated SPIONs to water without the need for separation from the crude reaction mixture. X-ray Rietveld refinement showed that particles obtained by this method had both the magnetite and wustite phases of iron oxide present. Magnetic measurements confirm that the iron oxide particles are superparamagnetic at room temperature, with typical blocking temperatures of 183 K for the spherical and 212 K for the cuboid ones.

Extremely small iron oxide nanoparticle (ESIONP)-based stimuli-responsive switchable MRI contrast agents (CAs) show great promise for accurate detection of tumors due to their outstanding advantages of high specificity and low background signal. However, currently developed ESIONP-based switchable CAs often suffer single-biomarker-induced responses, which lack absolute specificity to pathological tissues, potentially diminishing diagnostic accuracy. In this study, weak acidity and hypoxia, two of the most remarkable characteristics of tumors, are introduced as dual biomarker stimuli to construct an ESIONP-based switchable MRI CA (DKL-CA), with its signal switch controlled by a "dual-key-and-lock" strategy. Only when DKL-CA is exposed to a coexisting weakly acidic and hypoxic environment can monodispersed ESIONPs form nanoclusters, thereby realizing a switch from the T1 to T2 contrast. Moreover, DKL-CA exhibits favorable biosafety and the capacity for precise tumor diagnosis in tumor-bearing mice. Overall, DKL-CA paves the way for designing highly accurate ESIONP-based MRI CAs for tumor diagnosis.

Iron oxide nanoparticles (IONPs) have been cleared by the Food and Drug Administration (FDA) for various clinical applications, such as tumor-targeted imaging, hyperthermia therapy, drug delivery, and live-cell tracking. However, the application of IONPs as T1 contrast agents has been restricted due to their high r2 values and r2/r1 ratios, which limit their effectiveness in T1 contrast enhancement. Notably, IONPs with diameters smaller than 5 nm, referred to as extremely small-sized IONPs (ESIONs), have demonstrated potential in overcoming these limitations. To advance the clinical application of ESIONs as T1 contrast agents, we have refined a scale-up process for micelle encapsulation aimed at improving the hydrophilization of ESIONs, and have carried out comprehensive in vivo biodistribution and preclinical toxicity assessments.

The optimization of the scale-up micelle-encapsulation process, specifically employing Tween60 at a concentration of 10% v/v, resulted in ESIONs that were uniformly hydrophilized, with an average size of 9.35 nm and a high purification yield. Stability tests showed that these ESIONs maintained consistent size over extended storage periods and dispersed effectively in blood and serum-mimicking environments. Relaxivity measurements indicated an r1 value of 3.43 mM- 1s- 1 and a favorable r2/r1 ratio of 5.36, suggesting their potential as T1 contrast agents. Biodistribution studies revealed that the ESIONs had extended circulation times in the bloodstream and were primarily cleared via the hepatobiliary route, with negligible renal excretion. We monitored blood clearance and organ distribution using positron emission tomography and magnetic resonance imaging (MRI). Additionally, MRI signal variations in a dose-dependent manner highlighted different behaviors at varying ESIONs concentrations, implying that optimal dosages might be specific to the intended imaging application. Preclinical safety evaluations indicated that ESIONs were tolerable in rats at doses up to 25 mg/kg.

This study effectively optimized a scale-up process for the micelle encapsulation of ESIONs, leading to the production of hydrophilic ESIONs at gram-scale levels. These optimized ESIONs showcased properties conducive to T1 contrast imaging, such as elevated r1 relaxivity and a reduced r2/r1 ratio. Biodistribution study underscored their prolonged bloodstream presence and efficient clearance through the liver and bile, without significant renal involvement. The preclinical toxicity tests affirmed the safety of the ESIONs, supporting their potential use as T1 contrast agent with versatile clinical application.

Contrast-enhanced magnetic resonance angiography (CE-MRA) plays a critical role in diagnosing and monitoring various vascular diseases. Achieving high-sensitivity detection of vascular abnormalities in CE-MRA depends on the properties of contrast agents. In contrast to clinically used gadolinium-based contrast agents (GBCAs), the new generation of ultrasmall ferrite nanoparticles-based contrast agents have high relaxivity, long blood circulation time, easy surface functionalization, and high biocompatibility, hence showing promising prospects in CE-MRA. This review aims to comprehensively summarize the advancements in ultrasmall ferrite nanoparticles-enhanced MRA for detecting vascular diseases. Additionally, this review also discusses the future clinical translational potential of ultrasmall ferrite nanoparticles-based contrast agents for vascular imaging. By investigating the current status of research and clinical applications, this review attempts to outline the progress, challenges, and future directions of using ultrasmall ferrite nanoparticles to drive the field of CE-MRA into a new frontier of accuracy and diagnostic efficacy.

Stroke is responsible for 11% of all deaths worldwide, the majority of which are caused by ischemic strokes, thus making the need to urgently find safe and effective therapies. Today, these can be cured either by mechanical thrombectomy when the thrombus is accessible, or by intravenous injection of fibrinolytics. However, the latter present several limitations, such as potential severe side effects, few eligible patients and low rate of partial and full recovery. To design safer and more effective treatments, nanomedicine appeared in this medical field a few decades ago. This review will explain why nanoparticle-based therapies and imaging techniques are relevant for ischemic stroke management. Then, it will present the different nanoparticle types that have been recently developed to treat this pathology. It will also study the various targeting strategies used to bring nanoparticles to the stroke site, thereby limiting side effects and improving the therapeutic efficacy. Finally, this review will present the few clinical studies testing nanomedicine on stroke and discuss potential causes for their scarcity.

Patients with brain cancers including medulloblastoma lack treatments that are effective long-term and without side effects. In this study, a multifunctional fluoropolymer-engineered iron oxide nanoparticle gene-therapeutic platform is presented to overcome these challenges. The fluoropolymers are designed and synthesized to incorporate various properties including robust anchoring moieties for efficient surface coating, cationic components to facilitate short interference RNA (siRNA) binding, and a fluorinated tail to ensure stability in serum. The blood-brain barrier (BBB) tailored system demonstrates enhanced BBB penetration, facilitates delivery of functionally active siRNA to medulloblastoma cells, and delivers a significant, almost complete block in protein expression within an in vitro extracellular acidic environment (pH 6.7) - as favored by most cancer cells. In vivo, it effectively crosses an intact BBB, provides contrast for magnetic resonance imaging (MRI), and delivers siRNA capable of slowing tumor growth without causing signs of toxicity - meaning it possesses a safe theranostic function. The pioneering methodology applied shows significant promise in the advancement of brain and tumor microenvironment-focused MRI-siRNA theranostics for the better treatment and diagnosis of medulloblastoma.

Ultrasmall mesoporous nanoparticles (<50 nm), a unique porous nanomaterial, have been widely studied in many fields in the last decade owing to the abundant advantages, involving rich mesopores, low density, high surface area, numerous reaction sites, large cavity space, ultrasmall size, etc. This paper presents a review of recent advances in the preparation, functionalization, and applications of ultrasmall inorganic mesoporous nanoparticles for the first time. The soft monomicelles-directed method, in contrast to the hard-template and template-free methods, is more flexible in the synthesis of mesoporous nanoparticles. This is because the amphiphilic micelle has tunable functional blocks, controlled molecule masses, configurations and mesostructures. Focus on the soft micelle directing method, monomicelles could be classified into four types, i.e., the Pluronic-type block copolymer monomicelles, laboratory-synthesized amphiphilic block copolymers monomicelles, the single-molecule star-shaped block copolymer monomicelles, and the small-molecule anionic/cationic surfactant monomicelles. This paper also reviews the functionalization of the inner mesopores and the outer surfaces, which includes constructing the yolkshell structures (encapsulated nanoparticles), anchoring the active components packed on the shell and building an asymmetric Janus architecture. Then, several representative applications, involving catalysis, energy storage, and biomedicines are presented. Finally, the prospects and challenges of controlled synthesis and large-scale applications of ultrasmall mesoporous nanoparticles in the future are foreseen.

The identification of metastasis "seeds," isolated tumor cells (ITCs), is of paramount importance for the prognosis and tailored treatment of metastatic diseases. The conventional approach to clinical ITCs diagnosis through invasive biopsies is encumbered by the inherent risks of overdiagnosis and overtreatment. This underscores the pressing need for noninvasive ITCs detection methods that provide histopathological-level insights. Recent advancements in ultra-high-field (UHF) magnetic resonance imaging (MRI) have ignited hope for the revelation of minute lesions, including the elusive ITCs. Nevertheless, currently available MRI contrast agents are susceptible to magnetization-induced strong T2-decaying effects under UHF conditions, which compromises T1 MRI capability and further impedes the precise imaging of small lesions. Herein, this study reports a structural defect-enabled magnetic neutrality nanoprobe (MNN) distinguished by its paramagnetic properties featuring an exceptionally low magnetic susceptibility through atomic modulation, rendering it almost nonmagnetic. This unique characteristic effectively mitigates T2-decaying effect while concurrently enhancing UHF T1 contrast. Under 9 T MRI, the MNN demonstrates an unprecedentedly low r2/r1 value (≈1.06), enabling noninvasive visualization of ITCs with an exceptional detection threshold of ≈0.16 mm. These high-performance MNNs unveil the domain of hitherto undetectable minute lesions, representing a significant advancement in UHF-MRI for diagnostic purposes and fostering comprehensive metastasis research.

Bimetallic iron-noble metal alloy nanoparticles have emerged as promising contrast agents for magnetic resonance imaging (MRI) due to their biocompatibility and facile control over the element distribution. However, the inherent surface energy discrepancy between iron and noble metal often leads to Fe atom segregation within the nanoparticle, resulting in limited iron-water molecule interactions and, consequently, diminished relaxometric performance. In this study, we present the development of a class of ligand-induced atomically segregation-tunable alloy nanoprobes (STAN) composed of bimetallic iron-gold nanoparticles. By manipulating the oxidation state of Fe on the particle surface through varying molar ratios of oleic acid and oleylamine ligands, we successfully achieve surface Fe enrichment. Under the application of a 9 T MRI system, the optimized STAN formulation, characterized by a surface Fe content of 60.1 at %, exhibits an impressive r1 value of 2.28 mM-1·s-1, along with a low r2/r1 ratio of 6.2. This exceptional performance allows for the clear visualization of hepatic tumors as small as 0.7 mm in diameter in vivo, highlighting the immense potential of STAN as a next-generation contrast agent for highly sensitive MR imaging.

Iron oxide nanoparticles are a type of nanomaterial composed of iron oxide (Fe3O4 or Fe2O3) and have a wide range of applications in magnetic resonance imaging. Compared to iron oxide nanoparticles, extremely small iron oxide nanoparticles (ESIONPs) (∼3 nm in diameter) can improve the imaging performance due to a smaller size. However, there are currently no reports on the potential toxic effects of ESIONPs on the human body. In this study, we applied ESIONPs to a zebrafish model and performed weighted gene co-expression network analysis (WGCNA) on differentially expressed genes (DEGs) in zebrafish embryos of 48 hpf, 72 hpf, 96 hpf, and 120 hpf using RNA-seq technology. The key hub genes related to neurotoxicity and ferroptosis were identified, and further experiments also demonstrated that ESIONPs impaired the neuronal and muscle development of zebrafish, and induced ferroptosis, leading to oxidative stress, cell apoptosis, and inflammatory response. Here, for the first time, we analyzed the potential toxic effects of ESIONPs through WGCNA. Our studies indicate that ESIONPs might have neurotoxicity and could induce ferroptosis, while abnormal accumulation of iron ions might increase the risk of early degenerative neurological diseases.

Highly sensitive iron oxide nanoparticles with stable, safe and efficient surface functionalization, as potential substitutes for gadolinium-based contrast agents (GBCAs) with increasing biosafety concerns, exhibit great potential for high-performance magnetic resonance angiography (MRA). Herein, we developed ultrasmall catechol-PEG-anchored ferrite nanoparticles (PEG-UMFNPs) for highly sensitive MRA. The obtained nanoprobe has a high T1 relaxivity value (7.2 mM-1 s-1) due to its ultrasmall size and Mn doping. It has a suitable hydrodynamic size of 20 nm, which prevents rapid vascular extravasation and renal clearance and prolongs its blood circulation time. In vivo MRA at 3.0 T using the nanoprobe shows that the arteries and veins of rats, even blood vessels as small as 0.32 mm, are distinctly visible, and the contrast enhancement can last for at least 1 h. In addition, due to the outstanding contrast enhancement and long circulation time, the stenosis and recanalization process of the rat's carotid artery can be continuously monitored with a single injection of the nanoprobe. Our study indicates that PEG-UMFNPs are outstanding MR imaging nanoprobes that can be used to diagnose vascular diseases without the biosafety issues of GBCAs.

We report the controlled synthesis of iron oxide microcubes (IOMCs) through the self-assembly arrays of ferric oxide hydroxide nanorods (NRs). The formation of IOMCs involves a complex interplay of nucleation, self-assembly, and growth mechanisms influenced by time, thermal treatment, and surfactant dynamics. The self-assembly of vertically aligned NRs into IOMCs is controlled by dynamic magnetism properties and capping agents like cetyltrimethylammonium bromide (CTAB), whose concentration and temperature modulation dictate growth kinetics and structural uniformity. These controlled structural growths were obtained via a hydrothermal process at 120 °C at various intervals of 8, 16, 24, and 32 h in the presence of CTAB as the capping agent. In this hydrothermal method, the formation of vertically oriented NR arrays was observed without the presence of ligands, binders, harsh drying techniques, and solvent evaporation. The formation of the self-assembly of NRs to IOMCs is obtained with an increase in saturated magnetization to attain the most stable state. The synthesized IOMCs have a uniform size, quasi-shape, and excellent dispersion. Due to its excellent magnetic and catalytic properties, IOMCs were employed to remove the various emerging pollutants known as per- and polyfluorinated substances (PFAS). Various microscopic and spectroscopic techniques were employed for the characterization and interaction studies of IOMCs with various PFAS. The interaction between IOMCs and perfluoroalkyl substances (PFAS) was investigated, revealing strong adsorption tendencies facilitated by electrostatic interactions, as evidenced by UV-vis and FT-IR spectroscopic studies. Furthermore, the higher magnetic and positive surface charge of IOMCs is responsible for an effective remediation eliminating any secondary pollution with ease of recovery after the sorption interaction studies, thereby making it practically worthwhile.

The general sluggish clearance kinetics of functional inorganic nanoparticles tend to raise potential biosafety concerns for in vivo applications. Renal clearance is a possible elimination pathway for functional inorganic nanoparticles delivered through intravenous injection, but largely depending on the surface physical chemical properties of a given particle apart from its size and shape.

In this study, three small-molecule ligands that bear a diphosphonate (DP) group, but different terminal groups on the other side, i.e., anionic, cationic, and zwitterionic groups, were synthesized and used to modify ultrasmall Fe3O4 nanoparticles for evaluating the surface structure-dependent renal clearance behaviors. Systematic studies suggested that the variation of the surface ligands did not significantly increase the hydrodynamic diameter of ultrasmall Fe3O4 nanoparticles, nor influence their magnetic resonance imaging (MRI) contrast enhancement effects. Among the three particle samples, Fe3O4 nanoparticle coated with zwitterionic ligands, i.e., Fe3O4@DMSA, exhibited optimal renal clearance efficiency and reduced reticuloendothelial uptake. Therefore, this sample was further labeled with 99mTc through the DP moieties to achieve a renal-clearable MRI/single-photon emission computed tomography (SPECT) dual-modality imaging nanoprobe. The resulting nanoprobe showed satisfactory imaging capacities in a 4T1 xenograft tumor mouse model. Furthermore, the biocompatibility of Fe3O4@DMSA was evaluated both in vitro and in vivo through safety assessment experiments.

We believe that the current investigations offer a simple and effective strategy for constructing renal-clearable nanoparticles for precise disease diagnosis.