Alzheimer's disease (AD) remains an incurable disease and lacks efficient diagnostic methods. Most AD treatments have focused on amyloid-β (Aβ) targeted therapy; however, it is time to consider the alternative theranostics due to accumulated findings of weak correlation between Aβ deposition and cognition, as well as the failures of Phase III clinical trial on Aβ targeted therapy. Recent studies have shown that the tau pathway is closely associated with clinical development of AD symptoms, which might be a potential therapeutic target. We herein construct a methylene blue (MB, a tau aggregation inhibitor) loaded nanocomposite (CeNC/IONC/MSN-T807), which not only possesses high binding affinity to hyperphosphorylated tau but also inhibits multiple key pathways of tau-associated AD pathogenesis. We demonstrate that these nanocomposites can relieve the AD symptoms by mitigating mitochondrial oxidative stress, suppressing tau hyperphosphorylation, and preventing neuronal death both in vitro and in vivo. The memory deficits of AD rats are significantly rescued upon treatment with MB loaded CeNC/IONC/MSN-T807. Our results indicate that hyperphosphorylated tau-targeted multifunctional nanocomposites could be a promising therapeutic candidate for Alzheimer's disease.

Smart magnetic resonance (MR) contrast agents, by which MR contrast can be selectively enhanced under acidic tumor microenvironment, are anticipated to significantly improve the diagnostic accuracy. Here, we report pH-sensitive iron oxide nanoparticle assemblies (IONAs) that are cross-linked by small-molecular aldehyde derivative ligands. The dynamic formation and cleavage of hydrazone linkages in neutral and acidic environments, respectively, allow the reversible response of the nanoassemblies to pH variations. At neutral pH, IONAs are structurally robust due to the cross-linking by the strong hydrazone bonds. In acidic tumor microenvironment, the hydrazone bonds are cleaved so that the IONAs are quickly disassembled into a large number of hydrophilic extremely small-sized iron oxide nanoparticles (ESIONs). As a result, significantly enhanced T1MR contrast is achieved, as confirmed by the measurement of r1 values at different pH conditions. Such acidity-targeting MR signal amplification by the pH-sensitive IONAs was further validated in vivo, demonstrating a novel T1 magnetic resonance imaging (MRI) strategy for highly sensitive imaging of acidic tumors.

Stem cell therapies are increasingly recognized as the future direction of regenerative medicine, but the biological fate of the administrated stem cells remains a major concern for clinical translation, which calls for an approach to efficiently monitoring the stem cell behaviors in vivo. Magnetic particle imaging (MPI) is an emerging technology for cell tracking; however, its utility has been largely restricted due to the lack of optimal magnetic nanoparticle tracers. Herein, by controlled engineering of the size and shape of magnetic nanoparticles tailored to MPI physics theory, a specialized MPI tracer, based on cubic iron oxide nanoparticles with an edge length of 22 nm (CIONs-22), is developed. Due to the inherent lower proportion of disordered surface spins, CIONs-22 exhibit significantly larger saturation magnetization than that of spherical ones, while they possess similar saturation magnetization but smaller coercivity compared to larger-sized CIONs. These magnetic properties of CIONs-22 warrant high sensitivity and resolution of MPI. With their efficient cellular uptake, CIONs-22 exhibit superior MPI performance for stem cell labeling and tracking compared to the commercialized tracer Vivotrax. By virtue of these advantages, CIONs-22 enable real-time and prolonged monitoring of the spatiotemporal trajectory of stem cells transplanted to hindlimb ischemia mice, which demonstrates the great potential of CIONs-22 as MPI tracers to advance stem cell therapies. KEYWORDS: magnetic particle imaging, cubic iron oxide nanoparticle, bone mesenchymal stem cell, stem cell tracking, hindlimb ischemia S tem-cell-based therapies have demonstrated therapeutic potential for a wide spectrum of diseases, such as hindlimb ischemia, stroke, liver disease, and heart failure. 1,2 However, to ultimately advance this fast growing field from preclinical studies to translation, several major concerns are yet to be addressed, one of which is the poorly understood biological fate of injected stem cells, e.g., the timing and path of their migration to diseased tissues. In this regard, it is of particular relevance to monitor stem cells after administration into the body, which would provide valuable information for predicting the therapeutic efficacy, evaluating the potential risk, and optimizing treatment strategies. 3 Current technologies for in vivo stem cell tracking include optical imaging, magnetic resonance imaging (MRI), and radionuclide imaging. 4−7 Optical imaging has single-cell resolution, but its clinical translation is hindered by the poor tissue penetration of the light photon. 8 Radionuclide imaging, with excellent depth penetration, faces the disadvantage of narrow temporal window due to the short half-lives of radionuclide tracers that are also constantly questioned for toxicities. 9,10 MRI offers high spatial resolution and unlimited depth penetration without using radiotracers. 8 However, the dark signal generated by T2-weighed MRI contrast agents (CAs) (e.g., iron oxide nanoparticles (IONPs)) 11,12 can be easil...

Unsatisfactory post-stroke recovery has long been a negative factor in the prognosis of ischemic stroke due to the lack of pharmacological treatments. Mesenchymal stem cells (MSCs)-based therapy has recently emerged as a promising strategy redefining stroke treatment; however, its effectiveness has been largely restricted by insufficient therapeutic gene expression and inadequate cell numbers in the ischemic cerebrum. Herein, a non-viral and magnetic field-independent gene transfection approach is reported, using magnetosome-like ferrimagnetic iron oxide nanochains (MFIONs), to genetically engineer MSCs for highly efficient post-stroke recovery. The 1D MFIONs show efficient cellular uptake by MSCs, which results in highly efficient genetic engineering of MSCs to overexpress brainderived neurotrophic factor for treating ischemic cerebrum. Moreover, the internalized MFIONs promote the homing of MSCs to the ischemic cerebrum by upregulating CXCR4. Consequently, a pronounced recovery from ischemic stroke is achieved using MFION-engineered MSCs in a mouse model.

The assessment of vascular anatomy and functions using magnetic resonance imaging (MRI) is critical for medical diagnosis, whereas the commonly used low‐field MRI system (≤3 T) suffers from low spatial resolution. Ultrahigh field (UHF) MRI (≥7 T), with significantly improved resolution and signal‐to‐noise ratio, shows great potential to provide high‐resolution vasculature images. However, practical applications of UHF MRI technology for vascular imaging are currently limited by the low sensitivity and accuracy of single‐mode (T1 or T2) contrast agents. Herein, a UHF‐tailored T1–T2 dual‐mode iron oxide nanoparticle‐based contrast agent (UDIOC) with extremely small core size and ultracompact hydrophilic surface modification, exhibiting dually enhanced T1–T2 contrast effect under the 7 T magnetic field, is reported. The UDIOC enables clear visualization of microvasculature as small as ≈140 µm in diameter under UHF MRI, extending the detection limit of the 7 T MR angiography. Moreover, by virtue of high‐resolution UHF MRI and a simple double‐checking process, UDIOC‐based dual‐mode dynamic contrast‐enhanced MRI is successfully applied to detect tumor vascular permeability with extremely high sensitivity and accuracy, providing a novel paradigm for the precise medical diagnosis of vascular‐related diseases.

Histopathological level imaging in a non-invasive manner is important for clinical diagnosis, which has been a tremendous challenge for current imaging modalities. Recent development of ultra-high-field (UHF) magnetic resonance imaging (MRI) represents a large step toward this goal. Nevertheless, there is a lack of proper contrast agents that can provide superior imaging sensitivity at UHF for disease detection, because conventional contrast agents generally induce T2 decaying effects that are too strong and thus limit the imaging performance. Herein, by rationally engineering the size, spin alignment, and magnetic moment of the nanoparticles, we develop an UHF MRI-tailored ultra-sensitive antiferromagnetic nanoparticle probe (AFNP), which possesses exceptionally small magnetisation to minimize T2 decaying effect. Under the applied magnetic field of 9 T with mice dedicated hardware, the nanoprobe exhibits the ultralow r2/r1 value (~1.93), enabling the sensitive detection of microscopic primary tumours (<0.60 mm) and micrometastases (down to 0.20 mm) in mice. The sensitivity and accuracy of AFNP-enhanced UHF MRI are comparable to those of the histopathological examination, enabling the development of non-invasive visualization of previously undetectable biological entities critical to medical diagnosis and therapy.

Contrast agents can improve the sensitivity and resolution of magnetic resonance imaging (MRI) by accelerating the relaxation times of surrounding water protons. The MRI performances of contrast agents are closely related to their structural characteristics, including size, shape, surface modification, and so on. Recently, dynamically switchable MRI contrast agents that can undergo structural changes and imaging functional activations upon reaching the disease microenvironment have been developed for high performance MRI. This perspective highlights the ingenious design, controllable structural transformation, and tunable imaging property of dynamic MRI contrast agents. Additionally, the current challenges of the dynamic MRI contrast agents for medical diagnosis are discussed. Furthermore, the future integration of high-resolution ultra-high field MRI technology and cutting-edge dynamic MRI contrast agents for non-invasive histopathological level accurate detection of microscopic lesions are commented.

The COVID-19 outbreak is under control in China. Mobility interventions, including both the Wuhan lockdown and travel restrictions in other cities, have been undertaken in China to mitigate the epidemic. However, the impact of mobility restrictions in cites outside Wuhan has not been systematically analyzed. Here we ascertain the relationships between all mobility patterns and the epidemic trajectory in Chinese cities outside Hubei Province, and we estimate the impact of local travel restrictions. We estimate local inter-city travel bans averted 22.4% (95% PI: 16.8-27.9%) more infections in the two weeks after the Wuhan lockdown, while local intracity travel prevented 32.5% (95% PI: 18.9-46.1%) more infections in the third and fourth weeks.More synchronized implementation of mobility interventions would further decrease the number . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) : medRxiv preprint of confirmed cases in the first two weeks by 15.7% (95% PI:15.4-16.0%). This study shows synchronized travel restrictions across cities can be effective in COVID-19 control.