Ultrasmall catechol-PEG-anchored ferrite nanoparticles for highly sensitive magnetic resonance angiography.

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.

Long-circulating nanoparticles as passive targeting nanocarriers for the treatment of thrombosis.

Thrombosis is the major cause of cardiovascular diseases. Only a small subset of patients could benefit from thrombolytic therapy due to the high bleeding risk brought about by the repeated administration of thrombolytic drugs. Nanoparticles with targeting ligands have been developed as nanocarriers of thrombolytic drugs to deliver the drug to the thrombus through active targeting. However, the passive targeting effect of nanoparticles on the thrombus is yet to be investigated. Herein, we prepared silica cross-linked micelles (SCLMs) with a long blood circulation half-life as drug carriers to target the thrombus through passive targeting. Compared with SCLMs modified with an active targeting ligand cRGD, the SCLMs exhibited similar targeting behavior to the thrombus in vivo. Loaded with the thrombolytic drug tirofiban, the passive targeting SCLMs showed a comparable therapeutic effect to cRGD-modified SCLMs in a mice model with pulmonary embolism and arterial thrombosis.

Purification-free synthesis of bright lactoglobulin@dye nanoprobe for second near-infrared fluorescence imaging of kidney dysfunction in vivo.

Kidney disease is currently prevalent worldwide but only shows insidious symptoms in the early stages. The second near-infrared window (NIR-II) fluorescence imaging has become a widely used preclinical technology for evaluating renal dysfunction due to its high resolution and sensitivity. However, bright renal clearable NIR-II fluorescence nanoprobes with a simple synthesis process are still lacking. Herein, we develop a lactoglobulin (LG)@dye nanoprobe for NIR-II fluorescence imaging of kidney dysfunction in vivo based on a purification-free method. The nanoprobe was synthesized by simply mixing LG and IR820 in aqueous solutions at 70 °C for 2 h based on the covalent interaction between the meso-Cl in IR820 and LG. The synthesized LG@IR820 nanoprobe has bright and stable NIR-II fluorescence, ultra-small size (<5 nm), low toxicity, and renal-clearable ability. The high reaction efficiency and pure aqueous reaction media make the synthesis method purification-free. In a unilateral ureteral obstruction mouse model, incipient renal dysfunction assessment was achieved by LG@IR820 nanoprobe, which couldn't be diagnosed with conventional kidney function indicators. This study provides a bright and purification-free NIR-II LG@IR820 nanoprobe to visualize kidney dysfunction at the early stage.

Noninvasive Diagnosis of Kidney Dysfunction Using a Small-Molecule Manganese-Based Magnetic Resonance Imaging Probe.

Contrast-enhanced magnetic resonance imaging (CE-MRI) is a promising approach for the diagnosis of kidney diseases. However, safety concerns, including nephrogenic systemic fibrosis, limit the administration of gadolinium (Gd)-based contrast agents (GBCAs) in patients who suffer from renal impairment. Meanwhile, nanomaterials meet biosafety concerns because of their long-term retention in the body. Herein, we propose a small-molecule manganese-based imaging probe Mn-PhDTA as an alternative to GBCAs to assess renal insufficiency for the first time. Mn-PhDTA was synthesized via a simple three-step reaction with a total yield of up to 33.6%, and a gram-scale synthesis can be realized. Mn-PhDTA has an r1 relaxivity of 2.72 mM-1 s-1 at 3.0 T and superior kinetic inertness over Gd-DTPA and Mn-EDTA with a dissociation time of 60 min in the presence of excess Zn2+. In vivo and in vitro experiments demonstrate their good stability and biocompatibility. In the unilateral ureteral obstruction rats, Mn-PhDTA provided significant MR signal enhancement, enabled distinguishing structure changes between the normal and damaged kidneys, and evaluated the renal function at different injured stages. Mn-PhDTA could act as a potential MRI contrast agent candidate for the replacement of GBCAs in the early detection of kidney dysfunction and analysis of kidney disease progression.

Nonmetallic graphite for tumor magnetic hyperthermia therapy.

Magnetic hyperthermia therapy (MHT) has garnered immense interest due to its exceptional spatiotemporal specificity, minimal invasiveness and remarkable tissue penetration depth. Nevertheless, the limited magnetothermal heating capability and the potential toxicity of metal ions in magnetic materials based on metallic elements significantly impede the advancement of MHT. Herein, we introduce the concept of nonmetallic materials, with graphite (Gra) as a proof of concept, as a highly efficient and biocompatible option for MHT of tumors in vivo for the first time. The Gra exhibits outstanding magnetothermal heating efficacy owing to the robust eddy thermal effect driven by its excellent electrical conductivity. Furthermore, being composed of carbon, Gra offers superior biocompatibility as carbon is an essential element for all living organisms. Additionally, the Gra boasts customizable shapes and sizes, low cost, and large-scale production capability, facilitating reproducible and straightforward manufacturing of various Gra implants. In a mouse tumor model, Gra-based MHT successfully eliminates the tumors at an extremely low magnetic field intensity, which is less than one-third of the established biosafety threshold. This study paves the way for the development of high-performance magnetocaloric materials by utilizing nonmetallic materials in place of metallic ones burdened with inherent limitations.

Bioinspired BSA@polydopamine@Fe Nanoprobe with Self-Purification Capacity for Targeted Magnetic Resonance Imaging of Acute Kidney Injury.

Contrast-enhanced magnetic resonance imaging (CE-MRI) of acute kidney injury (AKI) is severely hindered by the poor targeting capacity and potential toxicity of current contrast agents. Herein, we propose one-step fabrication of a bovine serum albumin@polydopamine@Fe (BSA@PDA@Fe, BPFe) nanoprobe with self-purification capacity for targeted CE-MRI of AKI. BSA endows the BPFe nanoprobe with renal tubule-targeting ability, and PDA is capable of completely inhibiting the intrinsic metal-induced reactive oxygen species (ROS), which are always involved in Fe/Mn-based agents. The as-prepared nanoprobe owns a tiny size of 2.7 nm, excellent solubility, good T1 MRI ability, superior biocompatibility, and powerful antioxidant capacity. In vivo CE-MRI shows that the BPFe nanoprobe can accumulate in the renal cortex due to the reabsorption effect toward the serum albumin. In the AKI model, impaired renal reabsorption function can be effortlessly detected via the diminishment of renal cortical signal enhancement. More importantly, the administration of the BPFe nanoprobe would not aggravate renal damage of AKI due to the outstanding self-purification capacity. Besides, the BPFe nanoprobe is employed for CE-MR angiography to visualize fine vessel structures. This work provides an MRI contrast agent with good biosafety and targeting ability for CE-MRI of kidney diseases.

Highly Sensitive Early Diagnosis of Kidney Damage Using Renal Clearable Zwitterion-Coated Ferrite Nanoprobe via Magnetic Resonance Imaging In Vivo.

Iron oxide nanoprobes exhibit substantial potential in magnetic resonance imaging (MRI) of kidney diseases and can eliminate the nephrotoxicity of gadolinium-based contrast agents (GBCAs). Nevertheless, there is an extreme shortage of highly sensitive and renal clearable iron oxide nanoprobes suitable for early kidney damage detection through MRI. Herein, a renal clearable ultra-small ferrite nanoprobe (UMFNPs@ZDS) is proposed for highly sensitive early diagnosis of kidney damage via structural and functional MRI in vivo for the first time. The nanoprobe comprises a ferrite core coated with a zwitterionic layer, and possesses a high T1 relaxivity (12.52 mm-1s-1), a small hydrodynamic size (6.43 nm), remarkable water solubility, excellent biocompatibility, and impressive renal clearable ability. In a rat model of unilateral ureteral obstruction (UUO), the nanoprobe-based MRI can not only accurately visualize the locations of renal injury, but also provide comprehensive functional data including peak value, peak time, relative renal function (RRF), and clearance percentage via MRI. The findings prove the immense potential of ferrite nanoprobes as a superior alternative to GBCAs for the early diagnosis of kidney damage.

Noninvasive Assessment of Kidney Injury by Combining Structure and Function Using Artificial Intelligence-Based Manganese-Enhanced Magnetic Resonance Imaging.

Contrast-enhanced magnetic resonance imaging (MRI) is seriously limited in kidney injury detection due to the nephrotoxicity of clinically used gadolinium-based contrast agents. Herein, we propose a noninvasive method for the assessment of kidney injury by combining structure and function information based on manganese (Mn)-enhanced MRI for the first time. As a proof of concept, the Mn-melanin nanoprobe with good biocompatibility and excellent T1 relaxivity is applied in MRI of a unilateral ureteral obstruction mice model. The abundant renal structure and function information is obtained through qualitative and quantitative analysis of MR images, and a brand new comprehensive assessment framework is proposed to precisely identify the degree of kidney injury successfully. Our study demonstrates that Mn-enhanced MRI is a promising approach for the highly sensitive and biosafe assessment of kidney injury in vivo.

Magnetic Resonance Angiography with Hour-Scale Duration after Single Low-Dose Administration of Biocompatible Gadolinium Oxide Nanoprobe.

Long-term contrast-enhanced angiography offers significant advantages in theranostics for diverse vascular diseases, particularly in terms of real-time dynamic monitoring during acute vascular events; However, achieving vascular imaging with a duration of hours through a single administration of low-dose contrast agent remains challenging. Herein, a hyaluronic acid-templated gadolinium oxide (HA@Gd2O3) nanoprobe-enhanced magnetic resonance angiography (MRA) is proposed to address this bottleneck issue for the first time. The HA@Gd2O3 nanoprobe synthesized from a facile one-pot biomineralization method owns ultrasmall size, good biocompatibility, optimal circulation half-life (≈149 min), and a relatively high T1 relaxivity (r1) under both clinical 3 T (8.215 mM-1s-1) and preclinical 9.4 T (4.023 mM-1s-1) equipment. The HA@Gd2O3 nanoprobe-enhanced MRA highlights major vessels readily with significantly improved contrast, extended imaging duration for at least 2 h, and ultrahigh resolution of 0.15 mm under 9.4 T, while only requiring half clinical dosage of Gd. This technique can enable rapid diagnosis and real-time dynamic monitoring of vascular changes in a model of acute superior mesenteric vein thrombosis with only a single injection of nanoprobe. The HA@Gd2O3 nanoprobe-enhanced MRA provides a sophisticated approach for long-term (hour scale) vascular imaging with ultrahigh resolution and high contrast through single administration of low-dose contrast agent.

One-Minute Preparation of Iron Foam-Drug Implant for Ultralow-Power Magnetic Hyperthermia-Based Combination Therapy of Tumors in Vivo.

The magnetic hyperthermia-based combination therapy (MHCT) is a powerful tumor treatment approach due to its unlimited tissue penetration depth and synergistic therapeutic effect. However, strong magnetic hyperthermia and facile drug loading are incompatible with current MHCT platforms. Herein, an iron foam (IF)-drug implant is established in an ultra-facile and universal way for ultralow-power MHCT of tumors in vivo for the first time. The IF-drug implant is fabricated by simply immersing IF in a drug solution at an adjustable concentration for 1 min. Continuous metal structure of IF enables ultra-high efficient magnetic hyperthermia based on eddy current thermal effect, and its porous feature provides great space for loading various hydrophilic and hydrophobic drugs via "capillary action". In addition, the IF has the merits of low cost, customizable size and shape, and good biocompatibility and biodegradability, benefiting reproducible and large-scale preparation of IF-drug implants for biological application. As a proof of concept, IF-doxorubicin (IF-DOX) is used for combined tumor treatment in vivo and achieves excellent therapeutic efficacy at a magnetic field intensity an order of magnitude lower than the threshold for biosafety application. The proposed IF-drug implant provides a handy and universal method for the fabrication of MHCT platforms for ultralow-power combination therapy.

Metallic artifacts-free spectral computed tomography angiography based on renal clearable bismuth chelate.

Computed tomography angiography (CTA) is one of the most important diagnosis techniques for various vascular diseases in clinic. However, metallic artifacts caused by metal implants and calcified plaques in more and more patients severely hinder its wide applications. Herein, we propose an improved metallic artifacts-free spectral CTA technique based on renal clearable bismuth chelate (Bi-DTPA dimeglumine) for the first time. Bi-DTPA dimeglumine owns the merits of ultra-simple synthetic process, approximately 100% of yield, large-scale production capability, good biocompatibility, and favorable renal clearable ability. More importantly, Bi-DTPA dimeglumine shows superior contrast-enhanced effect in CTA compared with clinical iohexol at a wide range of X-ray energies especially in higher X-ray energy. In rabbits' model with metallic transplants, Bi-DTPA dimeglumine assisted-spectral CTA can not only effectively mitigate metallic artifacts by reducing beam hardening effect under high X-ray energy, but also enables accurate delineation of vascular structure. Our proposed strategy opens a revolutionary way to solve the bottleneck problem of metallic artifacts in CTA examinations.

Achieving Complete Tumor Clearance: A Minimalist Manganese Hydrogel for Magnetic Resonance Imaging-Guided Synergetic Microwave Ablation and Chemodynamic Therapy.

The combination of microwave ablation (MWA) and chemodynamic therapy (CDT) presents a promising strategy for complete eradication of residual tumor after MWA. However, it remains challenging and urgent to develop a facile, biocompatible, and imaging-guided platform for the achievement of this goal. Herein, a minimalist manganese hydrogel (ALG-Mn hydrogel) is proposed for synergistic MWA and CDT to completely eradicate tumor in vivo. The ALG-Mn hydrogel is prepared using a simple mixing method and exhibits excellent syringeability, remarkable microwave sensitivity, and potent Fenton-like activity. By assisting in MWA procedures, the ALG-Mn hydrogel enables both elimination of primary tumor mass through enhanced MWA efficacy and eradication of potential residual tumor tissues via robust CDT. This approach achieves complete tumor clearance without additional drug loading. Furthermore, the paramagnetic Mn2+ component allows real-time dynamic visualization of the ALG-Mn hydrogel at the tumor site via magnetic resonance imaging. To the best of knowledge, the proposed ALG-Mn hydrogel represents the minimalist biocompatible platform for imaging-guided synergistic MWA and CDT toward achieving complete tumor clearance.

Macrocyclic-Albumin Conjugates for Precise Delivery of Radionuclides and Anticancer Drugs to Tumors.

Precise delivery of radionuclides and anticancer drugs to tumor tissue is crucial to ensuring drug synergism and optimal therapeutic effects in radionuclide-based combination radio-chemotherapy. However, current codelivery vectors often rely on physical embedment/adsorption to load anticancer drugs, which lacks precise mechanisms for drug loading and release, resulting in unpredictable combination effects. Herein, a macrocyclic-albumin conjugate (MAC) that enables precise loading and controlled release of anticancer drugs is presented. By conjugating multiple macrocyclic hosts (sulfonate azocalix[4]arenes, SAC4A) to albumin molecules, the MAC facilitates the precise loading of anticancer drugs through host-guest interactions and site-specific labeling of radionuclides. Furthermore, the MAC degrades under hypoxic conditions, enabling the release of loaded drugs upon reaching tumor tissues. Through precise loading and targeted delivery of radionuclides and anticancer drugs, MAC achieves efficient cancer diagnosis and combined radio-chemotherapy in breast cancer cell (4T1)-bearing mice. Considering that SAC4A can load many anticancer drugs, MAC may provide a promising platform for effective combination radio-chemotherapy.

Non-invasive Diagnosis and Postoperative Evaluation of Carotid Artery Stenosis by BSA-Gd2O3 Nanoparticles-Based Magnetic Resonance Angiography.

Contrast-enhanced magnetic resonance angiography is a powerful and effective method to accurately diagnose carotid artery stenosis. Small molecular gadolinium (Gd)-based agents have reliable signal enhancement, but their short circulating time may result in a loss of image resolution due to insufficient vascular filling or contrast agent emptying. Here, we report an MRA imaging approach to diagnose carotid artery stenosis using long-circulating bovine serum albumin (BSA)-Gd2O3 nanoparticles (NPs). The BSA-Gd2O3 NPs synthesized by a simple biomineralization approach exhibit admirable monodispersity, uniform size, favorable aqueous solubility, good biocompatibility, and high relaxivity (14.86 mM-1 s-1 in water, 6.41 mM-1 s-1 in plasma). In vivo MRA imaging shows that outstanding vascular enhancement of BSA-Gd2O3 NPs (0.05 mmol Gd/kg, half the dose in the clinic) can be maintained for at least 2 h, much longer than Gd-DTPA. Vessels as small as 0.3 mm can be clearly observed in MRA images with high resolution. In a rat carotid artery stenosis model, the BSA-Gd2O3 NPs-based MRA enables the precise diagnosis of the severity and location and the therapeutic effect following the surgery of carotid artery stenosis, which provides a method for the theranostics of vascular diseases.

Advanced hitchhiking nanomaterials for biomedical applications.

Hitchhiking, a recently developed bio-inspired cargo delivery system, has been harnessed for diverse applications. By leveraging the interactions between nanoparticles and circulatory cells or proteins, hitchhiking enables efficient navigation through the vasculature while evading immune system clearance. Moreover, it allows for targeted delivery of nutrients to tissues, surveillance of the immune system, and pathogen elimination. Various synthetic nanomaterials have been developed to facilitate hitchhiking with circulatory cells or proteins. By combining the advantages of synthetic nanomaterials and circulatory cells or proteins, hitchhiking nanomaterials demonstrate several advantages over conventional vectors, including enhanced circulatory stability and optimized therapeutic efficacy. This review provides an overview of general strategies for hitchhiking, choices of cells and proteins, and recent advances of hitchhiking nanomaterials for biomedical applications.

Photoactivatable base editors for spatiotemporally controlled genome editing in vivo.

CRISPR-based base editors (BEs) are powerful tools for precise nucleotide substitution in a wide range of organisms, but spatiotemporal control of base editing remains a daunting challenge. Herein, we develop a photoactivatable base editor (Mag-ABE) for spatiotemporally controlled genome editing in vivo for the first time. The base editing activity of Mag-ABE can be activated by blue light for spatiotemporal regulation of both EGFP reporter gene and various endogenous genes editing. Meanwhile, the Mag-ABE prefers to edit A4 and A5 positions rather than to edit A6 position, showing the potential to decrease bystander editing of traditional adenine base editors. After integration with upconversion nanoparticles as a light transducer, the Mag-ABE is further applied for near-infrared (NIR) light-activated base editing of liver in transgenic reporter mice successfully. This study opens a promising way to improve the operability, safety, and precision of base editing.

Non-invasive diagnosis of acute kidney injury using Mn-doped carbon dots-based magnetic resonance imaging.

As Gd-based contrast agents suffer from the risk of causing nephrogenic systemic fibrosis, less toxic contrast agents are urgently needed in contrast-enhanced magnetic resonance imaging (CE-MRI) of kidney injury. Herein, we develop a non-invasive diagnosis method for acute kidney injury using CE-MRI based on manganese-doped carbon dots (Mn-CDs). The synthesized Mn-CDs possess an ultrasmall size of 5 nm, good biocompatibility, and a high T1 relaxation rate (10.8 mM-1 s-1), which can produce effective positive enhancement in the kidneys and clearly show the fine structures of the kidneys including the cortex, outer medulla, and inner medulla. In an acute kidney injury model, Mn-CDs-based CE-MRI can not only accurately and intuitively reveal the site of kidney injury consistent with the pathological analysis, but also reflect the functional changes in the injured kidney. Collectively, our study provides a new strategy for the non-invasive diagnosis of acute kidney injury using CE-MRI based on Mn-CDs.

Noninvasive Gastrointestinal Tract Imaging Using BSA-Ag2Te Quantum Dots as a CT/NIR-II Fluorescence Dual-Modal Imaging Probe in Vivo.

The combination of high-resolution computed tomography (CT) and the real-time sensitive second near-infrared window (NIR-II) fluorescence bioimaging can provide complementary information for the diagnosis, progression and prognosis of gastrointestinal disorders. Ag2Te quantum dots (QDs) are a kind of promising CT/NIR-II fluorescence dual-modal imaging probe due to their high atomic number and narrow bandgap. However, conventional Ag2Te QDs synthesized by oil phase approaches often suffer from complicated steps, harsh reaction conditions, and toxic organic solvents. Herein, we report the synthesis of bovine serum albumin (BSA)-Ag2Te QDs using a biomineralization approach for CT/NIR-II fluorescence dual-modal imaging of the gastrointestinal tract. The BSA-Ag2Te QDs are fabricated in a facile one-pot approach under mild conditions and exhibit homogeneous size, favorable monodispersity, admirable aqueous solubility, excellent X-ray attenuation properties, and outstanding NIR-II fluorescence performance. In vivo imaging experiments show that BSA-Ag2Te QDs can be used in gastrointestinal tract CT/NIR-II dual-modal imaging with high spatiotemporal resolution and sensitivity. In addition, in an intestinal obstruction mouse model, accurate lesion positioning and imaging-guided obstruction relief surgery are successfully realized based on BSA-Ag2Te QDs. Besides, BSA-Ag2Te QDs have outstanding biocompatibility in vitro and in vivo. This study presents a high-performance and biosafe CT/NIR-II fluorescence dual-modal imaging probe for visualizing the gastrointestinal tract in vivo.

Minimalist O2 generator formed by in situ KMnO4 oxidation for tumor cascade therapy.

Diverse oxygen generation strategies have been developed to overcome hypoxia in tumors for enhancing the therapeutic efficacy, but inevitably suffering from tedious synthesis process of oxygen generators in vitro before in vivo administration. Herein, we show direct injection of commercially and clinically used KMnO4 into solid tumors enables in situ formation of MnO2 as an oxygen depot for cascade oxidation damage and enhanced photodynamic therapy. KMnO4 can damage tumor tissues by oxidation and generate MnO2, and subsequent intravenous injection of Ce6 allows MnO2-triggered hypoxia-modulated photodynamic therapy of tumors. Excellent cascade tumor suppression effect is realized both in vitro and in vivo based on the KMnO4-Ce6 system without the need of synthesis. The proposed strategy lays down a novel way with unprecedented superiors of no need of synthesis process and ultra-facile administration procedure for tumor hypoxia-modulated cascade therapy.

Fabrication of gelatin Bi2S3 capsules as a highly sensitive X-ray contrast agent for gastrointestinal motility assessment in vivo.

Tiny BaSO4 rod-based X-ray imaging is the most frequently-used method for clinical diagnosis of gastrointestinal motility disorders. The BaSO4 rods usually have a small size to pass through the gastrointestinal tract smoothly, but suffer from unavoidably low sensitivity. Herein, we developed Bi2S3 capsules as a high-performance X-ray contrast agent for gastrointestinal motility assessment for the first time. The Bi2S3 capsules were synthesized by the encapsulation of commercial Bi2S3 powder into commercial gelatin capsules and subsequent coating of ultraviolet-curable resin. The prepared Bi2S3 capsules showed excellent biocompatibility in vitro and in vivo and superior X-ray attenuation ability due to the large atomic number and high K-edge value of Bi. The developed Bi2S3 capsules can serve as a small but highly sensitive X-ray contrast agent to quantitatively assess gastrointestinal motility in a vincristine-induced gastrointestinal motility disorder model in vivo by X-ray, CT and spectral CT imaging successfully, solving the intrinsic drawbacks of clinically used BaSO4.