ROS-responsive nanomodulators downregulate IFITM3 expression and eliminate ROS for Alzheimer's disease combination treatment.

Neuronal damage caused by ß-amyloid (Aß) aggregates and excess reactive oxygen species (ROS) is a crucial pathogenic event in Alzheimer's disease (AD). However, current Aß-targeting RNA interference (RNAi) treatments have shown limited therapeutic efficacy due to ineffective intracerebral siRNA delivery and overlooked crosstalk between excess ROS and Aß aggregates in the brain. Herein, a ROS-responsive nanomodulator (NM/CM) was developed for the combinational treatment of RNAi and ROS elimination for AD. NM/CM was coated with 4T1 cell membranes, which endowed NM/CM with the capability to cross blood-brain barrier (BBB). After being internalized by neural cells, NM/CM releases curcumin (Cur) and siIFITM3 spontaneously into the cytoplasm. The released Cur can eliminate ROS, protecting neurons from oxidative damage and reducing the production of Aß induced by ROS-related neuroinflammation. The released siIFITM3 can downregulate the expression of interferon-induced transmembrane protein 3 (IFITM3), thereby reducing the abnormal Aß production mediated by IFITM3. As a result, NM/CM remarkably alleviated ROS- and Aß aggregate-induced neurotoxicity in vitro, showing significant neuroprotective effects. This work demonstrates the potential of NM/CM in the development of novel and effective AD combination therapies.

Therapeutic nanosweepers promote ß-amyloid removal from the brain for Alzheimer's disease treatment.

Formation of neurotoxic ß-amyloid (Aß) deposits is generally believed to be a crucial pathogenic event in Alzheimer's disease (AD). However, current Aß-targeting medicines show limited therapeutic efficacy due to ineffective Aß removal and limited blood-brain barrier (BBB) penetration capability. Herein, a therapeutic nanosweeper (NS) with Aß removal capability is developed. NS can be efficiently loaded into neutrophils (NE) to form NS/NE to improve its BBB crossing efficiency and preserve its Aß removal capability after being released from neutrophils. With this capability, NS can be efficiently delivered into the brain in the form of NS/NE owing to its chemotaxis to inflammatory factors released from AD brain. Moreover, NS released from NS/NE preserved its Aß removal capability, thereby significantly alleviating the pathological symptoms of Aß deposition and neuronal apoptosis in AD mice. This work demonstrated the potential of NS in the development of novel and effective AD therapies.

NIRF turn-on nanoparticles based on the tumor microenvironment for monitoring intracellular protein delivery.

A dual responsive NIRF turn-on protein delivery system incorporating an NIRF turn-on probe and protein into one single nanoparticle has been constructed. It can be taken up efficiently by A549 cells, where protein release and NIRF recovery happen simultaneously in response to low pH and excessive H2O2. This work provides a novel system for monitoring intracellular protein delivery.

Facile fabrication of hypericin-entrapped glyconanoparticles for targeted photodynamic therapy.

BACKGROUND: Photodynamic therapy is a safe, noninvasive modality for cancer therapy, in which the photosensitizer (PS) is a crucial component. Hypericin (Hy) is a promising PS; however, its clinical application is significantly limited by its poor hydrophilicity. MATERIALS AND METHODS: To overcome the clinical application limitation of Hy, a novel strategy is developed here by entrapping Hy into polydopamine (PDA) film formed on the surface of magnetic iron oxide nanoparticles (MNPs) through the self-polymerization of dopamine under alkaline condition. The amount of Hy in the Hy-entrapped PDA-MNP composite nanoparticles (denoted as PHMs) was measured by spectrophotometry. Furthermore, lactose, as the targeting ligand to asialoglycoprotein receptors, was conjugated to the surface of the PHMs by taking advantage of the spontaneous reaction of PDA with amino groups. RESULTS: Spectrophotometry analysis revealed that the amount of Hy in the PHMs was 72 µmol g-1 PHMs. The fabricated Hy-entrapped glyconanoparticle (Lac-PHM) exhibited excellent water dispersibility, stability, and selectivity for asialoglycoprotein receptors overexpressing HepG2 cells. Atomic absorption spectroscopy analysis showed that the amount of the Lac-PHMs taken in HepG2 cells was 2.1-fold higher than that of the triethylene glycol-modified PHMs. The results of intracellular reactive oxygen species generation detection, cytotoxicity study, and apoptosis detection indicated that the Lac-PHMs had a satisfying photodynamic effect to HepG2 cells. CONCLUSION: The strategy developed in this work offers great potential for delivery of a variety of hydrophobic PSs.