The low specifi city and high risk of intracranial hemorrhage associated with currently approved thrombolytic therapies limit their effi cacy in recanalizing occluded vessels. Here, a nanoscale thrombolytic agent is demonstrated by immobilizing tissue plasminogen activator molecules (tPA) over 20 nm clustered iron oxide nanocubes (NCs). The resulting nanoconstructs (tPA-NCs) are capable of dissolving clots via both direct interaction of tPA with the fi brin network (chemical lysis) and localized hyperthermia upon stimulation of superparamagnetic NCs with alternating magnetic fi elds (AMFs) (mechanical lysis). In vitro, as compared to free tPA, the proposed nanoconstructs demonstrate a ≈100-fold increase in dissolution rate, possibly because of a more intimate interaction of tPA with the fi brin network. The clot dissolution rate is further enhanced (≈10-fold) by mild, localized heating resulting from the exposure of tPA-NCs to AMF. Intravital microscopy experiments demonstrate blood vessel reperfusion within a few minutes post tail vein injection of tPA-NCs. The proposed nanoconstructs also exhibit high transverse relaxivity (>400 × 10 -3 M −1 s −1 ) for magnetic resonance imaging. The multifunctional properties and the 3 orders of magnitude enhancement in clot dissolution make tPA-NCs a promising nano-theranosis agent in thrombotic disease.

Objective To determine the impact of hematopoietic deletion of nuclear factor− (erythroid-derived 2) like 2 factor (Nrf2) on the development of atherosclerosis and liver injury in an obese, hypercholesterolemic mouse model. Methods and Results Two-month-old male low-density lipoprotein receptor–deficient mice were lethally irradiated and transplanted with either wild type or Nrf2-deficient (Nrf2−/−) bone marrow cells. At 3 months of age, mice were placed on an obesogenic high-fat diet (HFD), high-cholesterol diet for 7 months. Despite no differences in body weight, body fat percentage, liver fat, plasma glucose, lipids, or insulin, the HFD-fed Nrf2−/− bone marrow recipients had increased proinflammatory vascular gene expression, a significant increase in atherosclerosis area (18% versus 28%; P=0.018) and lesion complexity, and a marked increase in liver fibrosis. The acceleration of vascular and liver injury may arise from enhanced macrophage migration, inflammation, and oxidative stress resulting from myeloid Nrf2 deficiency. Conclusion Myeloid-derived Nrf2 activity attenuates atherosclerosis development and liver inflammation and fibrosis associated with obesity. Prevention of oxidative stress in macrophage and other myeloid lineage cells may be an important therapeutic target to reduce inflammation-driven complications of obesity.

Multiple formulations of iron oxide nanoparticles (IONPs) have been proposed for enhancing contrast in magnetic resonance imaging (MRI) and for increasing efficacy in thermal ablation therapies. However, insufficient accumulation at the disease site and low magnetic performance hamper the clinical application of IONPs. Here, 20 nm iron oxide nanocubes were assembled into larger nanoconstructs externally stabilized by a serum albumin coating. The resulting assemblies of nanocubes (ANCs) had an average diameter of 100 nm and exhibited transverse relaxivity (r2 = 678.9 ± 29.0 mM‒1·s‒1 at 1.41 T) and heating efficiency (specific absorption rate of 109.8 ± 12.8 W·g‒1 at 512 kHz and 10 kA·m‒1). In mice bearing glioblastoma multiforme tumors, Cy5.5-labeled ANCs allowed visualization of malignant masses via both near infrared fluorescent and magnetic resonance imaging. Also, upon systemic administration of ANCs (5 mgFe·kg‒1), 30 min of daily exposure to alternating magnetic fields for three consecutive days was sufficient to halt tumor progression. This study demonstrates that intravascular administration of ANCs can effectively visualize and treat neoplastic masses.

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Growing evidence suggests that multifaceted diseases as cancer can be effectively tackled by hitting simultaneously different biological targets and monitoring patient‐specific responses. Combinatorial therapies, relying on the administration of two or more molecules with different cytotoxic mechanisms, are rapidly progressing in the clinic. Here, 100 nm spherical polymeric nanoconstructs (SPNs) are proposed for the combinatorial treatment of tumors by codelivering a potent antimitotic drug—docetaxel (DTXL)—and a broad spectrum anti‐inflammatory molecule—curcumin (CURC). In vitro, SPNs loaded with DTXL and CURC induce a threefold decrease in IC50 as compared to DTXL‐loaded SPNs. This synergic antitumor effect is also significant in mouse models of glioblastoma multiforme, where, after 22 d of treatment, the combinatorial approach leads to complete disease regression. At 90 d post‐treatment initiation, mice injected with DTXL + CURC SPNs have a 100% survival, whereas only 50% of the DTXL SPN treated mice survive. SPNs are also labeled with radioactive 64Cu(DOTA) molecules to document, via PET imaging, the progressive tumor mass shrinkage. Sensitization of DTXL by CURC is associated with NF‐κB downregulation and increased apoptosis. These theranostic nanoconstructs could be used for combinatorial treatment and assessment of therapeutic efficacy in other malignancies.