Remodeling of the liver fibrosis microenvironment based on nilotinib-loaded multicatalytic nanozymes with boosted antifibrogenic activity.

Liver fibrosis is a reversible pathological process caused by chronic liver damage and a major risk factor for hepatocellular carcinoma (HCC). Hepatic stellate cell (HSC) activation is considered the main target for liver fibrosis therapy. However, the efficiency of this strategy is limited due to the complex microenvironment of liver fibrosis, including excessive extracellular matrix (ECM) deposition and hypoxia-induced imbalanced ECM metabolism. Herein, nilotinib (NIL)-loaded hyaluronic acid (HA)-coated Ag@Pt nanotriangular nanozymes (APNH NTs) were developed to inhibit HSCs activation and remodel the microenvironment of liver fibrosis. APNH NTs efficiently eliminated intrahepatic reactive oxygen species (ROS) due to their inherent superoxide dismutase (SOD) and catalase (CAT) activities, thereby downregulating the expression of NADPH oxidase-4 (NOX-4) and inhibiting HSCs activation. Simultaneously, the oxygen produced by the APNH NTs further alleviated the hypoxic microenvironment. Importantly, the released NIL promoted collagen depletion by suppressing the expression of tissue inhibitor of metalloproteinase-1 (TIMP-1), thus synergistically remodeling the microenvironment of liver fibrosis. Notably, an in vivo study in CCl4-induced mice revealed that APNH NTs exhibited significant antifibrogenic effects without obvious long-term toxicity. Taken together, the data from this work suggest that treatment with the synthesized APNH NTs provides an enlightening strategy for remodeling the microenvironment of liver fibrosis with boosted antifibrogenic activity.

Orally Administrable H2 S-Scavenging Metal-Organic Framework Prepared by Co-Flow Microfluidics for Comprehensive Restoration of Intestinal Milieu.

Intestinal milieu disorders are strongly related to the occurrence of inflammatory bowel diseases (IBDs), which results from mucosa destruction, epithelium disruption, and tight junction (TJ) proteins loss. Excess of H2 S in the intestinal milieu produced by the sulfate-reducing bacteria metabolism contributes to development of IBDs via epithelial barrier breakdown. Conventional interventions, such as surgery and anti-inflammatory medications, are considered not completely effective because of frequent recurrence and other complications. Herein, a novel oral delivery system, a hydroxypropyl methylcellulose acetate succinate (HPMCAS)-based polymer-coated Zr-based metal-organic framework (UiO-66) with a Cux -rhodamine B (CR) probe (hereinafter referred to as HUR), is produced via a co-flow microfluidic approach with the ability to reduce H2 S levels, thus restoring the intestinal lumen milieu. HPMCAS serves as an enteric coating that exposes UiO-66@CR at the pH of the intestine but not the acidic pH of the stomach. The synthesized HUR exhibits notable therapeutic efficacy, including mucosa recovery, epithelium integrity restoration, and TJ proteins upregulation via H2 S scavenging to protect against intestinal barrier damage and microbiome dysbiosis. Thus, HUR is verified to be a promising theranostic platform able to decrease the H2 S content for intestinal milieu disorder treatment. The presented study therefore opens the door for further exploitation for IBDs therapy.

Triangular-shaped homologous heterostructure as photocatalytic H2S scavenger and macrophage modulator for rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic arthropathy causing cartilage destruction, bone erosion, and even disability. Although some advances in RA treatment have been made based on inflammatory cytokine inhibition, long-term treatment and drug effect have been restrained by severe side effects. Herein, we developed a resveratrol (RSV)-loaded Ag/Ag2S triangular-shaped homologous heterostructure with polyethylene glycol/folic acid (PEG/FA) modification (Ag/Ag2S-PEG-FA/RSV NTs) to simultaneously suppress inflammatory cytokine over-expression through photocatalytic H2S scavenging and macrophage polarization stimulation. On one hand, the over-expressed H2S, which acted as a pro-inflammatory mediator to activate the MAPK/ICAM-1 pathway and exacerbate inflammation, was eliminated through photocatalysis. The homologous Ag and Ag2S of the heterostructure enhanced electron separation and transfer by acting as a charge acceptor and electron generator, respectively, which restrained electron/hole recombination and promoted photocatalysis efficiency. Additionally, the intrinsic superoxide dismutase (SOD) and catalase (CAT) activity of Ag decomposed the reactive oxygen species (ROS) over-expressed in the RA microenvironment, which supplied O2 for the photocatalytic H2S scavenging progress. On the other hand, RSV, a natural product with anti-inflammatory activity, could be delivered to the inflammatory joint by the targeting effect of PEG-FA, thus inhibiting the IκB/NF-κB pro-inflammatory pathway to induce macrophage interconversion balance from M1 to M2. As expected, the Ag/Ag2S-PEG-FA/RSV NTs exhibited H2S scavenging capacity and modulated macrophage polarization to reduce the inflammatory cytokine level and halt RA progression in vitro and in vivo. Overall, this study revealed a therapeutic strategy with high efficacy, which opens broad prospects for RA treatment.

A painless and flexible bi-directional blood glucose-regulating system inspired by an inverter air conditioner.

Pursuing painless and flexible blood glucose regulation has been a century-long arduous mission. The current therapeutic systems can only regulate blood glucose unidirectionally (reduce), and the adjustment range is large, which is prone to the risk of hypoglycemia. Herein, inspired by the temperature fluctuation range controlled by the inverter air conditioner, we report a new bi-directional blood glucose-regulating drug delivery system (BDRS) consisting of glucose-loaded pressure-responsive nano-vesicles (Glu@PRNV), insulin-loaded black phosphorus nanosheets (Insulin@BPNs), hydrogel, and a painless blood sugar monitor patch. At first, BDRS could monitor blood glucose in real-time through visible color changes. Afterward, according to different requirements, BDRS could release glucose with the guidance of external pressure, or supplement insulin under near-infrared (NIR) irradiation, through which, the blood glucose level of diabetics could be accurately accommodated within a reasonable fluctuation range, thus minifying the likelihood of sudden hyperglycemia or hypoglycemia. Collectively, the supply-demand balance of blood glucose could be maintained via this real-time bi-directional drug delivery system, thereby improving the quality of life of diabetics. We have also verified the universality of this technique through a similar bi-directional sleep regulation.