CT/bioluminescence dual-modal imaging tracking of stem cells labeled with Au@PEI@PEG nanotracers and RfLuc in nintedanib-assisted pulmonary fibrosis therapy.

Mesenchymal stem cells (MSCs) are promising in idiopathic pulmonary fibrosis (IPF) therapy. However, low survival rate and ambiguous behavior of MSCs after transplantation impede their clinical translation. To this end, we have developed a new strategy to improve the survival rate and monitor the behavior of the transplanted MSCs simultaneously. In our strategy, nintedanib, a tyrosine kinase inhibitor, is employed to protect the human MSCs (hMSCs) from excessive oxidative stress responses and inflammatory environment in the damaged lung. Moreover, by labeling of the transplanted hMSCs with a computed tomography (CT) nanotracer, Au nanoparticles functionalized with polyethylenimine (PEI) and polyethylene glycol (PEG) (Au@PEI@PEG), in combination with red-emitting firefly luciferase (RfLuc), in vivo CT/bioluminescence (BL) dual-modal imaging tracking of the location, distribution, and survival of the transplanted hMSCs in presence of nintedanib were achieved, which facilitates the profound understanding of the role the stem cells play in IPF therapy.

Au-Pt nanozyme-based multifunctional hydrogel dressing for diabetic wound healing.

Diabetic chronic wound healing is a critical clinical challenge due to the particularity of wound microenvironment, including hyperglycemia, excessive oxidative stress, hypoxia, and bacterial infection. Herein, we developed a multifunctional self-healing hydrogel dressing (defined as OHCN) to regulate the complex microenvironment of wound for accelerative diabetic wound repair. The OHCN hydrogel dressing was constructed by integrating Au-Pt alloy nanoparticles into a hydrogel (OHC) that formed through Schiff-base reaction between oxidized hyaluronic acid (OHA) and carboxymethyl chitosan (CMCS). The dynamic cross-linking of OHA and antibacterial CMCS imparted the OHCN hydrogel dressing with excellent antibacterial and self-healing properties. Meanwhile, Au-Pt alloy nanoparticles endowed the OHCN hydrogel dressing with the functions of lowering blood glucose, alleviating oxidative damage, and providing O2 by simulating glucose oxidase and catalase. Through a synergistic combination of OHC hydrogel and Au-Pt alloy nanoparticles, the resulted OHCN hydrogel dressing significantly ameliorated the pathological microenvironment and accelerated the healing rate of diabetic wound. The proposed nanozyme-decorated multifunctional hydrogel offers an efficient strategy for the improved management of diabetic chronic wound.

Facile engineering of ECM-mimetic injectable dual crosslinking hydrogels with excellent mechanical resilience, tissue adhesion, and biocompatibility.

Injectable hydrogels have aroused ever-increasing interest for their cell/biomaterial delivery ability through minimally invasive procedures. Nevertheless, it is still a challenge to simply fabricate natural biopolymer-based injectable hydrogels possessing satisfactory mechanical properties, bioadhesion, and cell delivery ability. Herein, we describe a facile dual crosslinking (DC) strategy for preparing extracellular matrix (ECM) mimetic hydrogels with desirable comprehensive performance. The chondroitin sulfate (CS)- and gelatin (Gel)-based single crosslinked (SC) hydrogels were first developed via reversible borate ester bonds, and further strengthened through the Michael-addition crosslinking reaction or visible-light initiated photopolymerization with thiol-containing polyethylene glycol (PEG) crosslinkers. The dynamic SC hydrogels showed good injectability, pH-sensitive gel-sol transformation, and self-adhesion ability to various biological tissues such as skin, liver, and intervertebral disc. The mechanically tough DC hydrogels displayed tunable stiffness, and resilience to compression load (up to 90% strain) owing to the effective energy dissipation mechanism. The formed DC hydrogels after subcutaneous injection well integrated with surrounding tissues and exhibited fast self-recovery properties. Moreover, the photoencapsulation of human mesenchymal stem cells (hMSCs) within the developed DC hydrogels was achieved and has been proved to be biocompatible, highlighting the great potential of the photopolymerized DC hydrogels in cell delivery and three-dimensional (3D) cell culture. This biomimetic, mechanically resilient, adhesive, and cytocompatible injectable DC hydrogel could serve as a promising candidate for tissue engineering.

Improved oral delivery of insulin by PLGA nanoparticles coated with 5ß-cholanic acid conjugated glycol chitosan.

Oral insulin has been regarded as the best alternative to insulin injection in therapy of diabetes because of its convenience and painlessness. However, several obstacles in the gastrointestinal tract, such as gastric acid and enzyme, greatly reduce the bioavailability of oral insulin. Herein, we report design and preparation of poly (d, l-lactic-co-glycolic acid) nanoparticles (PLGA NPs) coated with 5ß-cholanic acid modified glycol chitosan (GC-CA) (GC-CA@PLGA NPs) to improve the oral delivery of insulin. The GC-CA@PLGA NPs with the size of (302.73 ± 5.13 nm) and zeta potential of (25.03 ± 0.31 mV) were synthesized using the double-emulsion method. The insulin-loading capacity and encapsulation efficiency were determined to be 5.77 ± 0.58% and 51.99 ± 5.27%, respectively. Compared with GC-modified PLGA NPs (GC@PLGA NPs) and bare PLGA NPs, the GC-CA@PLGA NPs showed excellent stability and uptake by Caco-2 cells after simulated gastric acid digestion. Further experiment suggests good biocompatibility of GC-CA@PLGA NPs, including hemolysis and cytotoxicity. Inin vivoexperiment, the insulin loaded in the GC-CA@PLGA NPs exhibited a long-term and stable release profile for lowering blood glucose and presented 30.43% bioavailability in oral administration. In brief, we have developed an efficient and safe drug delivery system, GC-CA@PLGA NPs, for significantly improved oral administration of insulin, which may find potential application in the treatment of diabetes.

Enhanced and long-term CT imaging tracking of transplanted stem cells labeled with temperature-responsive gold nanoparticles.

Gold nanoparticles (AuNPs) have been extensively employed for computed tomography (CT) imaging in cell labeling and tracking because of their strong X-ray attenuation coefficient and excellent biocompatibility. However, the design and synthesis of stimuli-responsive AuNPs to modulate their endocytosis and exocytosis for optimal cell labeling and tracking are promising but challenging. Herein, we report an innovative labeling strategy based on temperature-responsive AuNPs (TRAuNPs) with high cell labeling efficiency and extended intracellular retention duration. We have manifested that the TRAuNP labeling imposes a negligible adverse effect on the function of human mesenchymal stem cells (hMSCs). Further experiment with idiopathic pulmonary fibrosis (IPF) model mice has demonstrated the feasibility of TRAuNP labeling for long time CT imaging tracking of transplanted hMSCs. What's more, the survival of transplanted hMSCs could also be monitored simultaneously using bioluminescence imaging after the expression of luciferase reporter genes. Therefore, we believe that this dual-modal labeling and tracking strategy enables visualization of the transplanted hMSCs in vivo, which may provide an important insight into the role of stem cells in the IPF therapy.

Glycyrrhetinic acid-modified graphene oxide mediated siRNA delivery for enhanced liver-cancer targeting therapy.

Graphene oxide (GO) has attracted huge attention in biomedical field in recent years. However, limited attempts have been invested in utilizing GO on active targeted delivery for gene therapy in liver cancer treatments. Glycyrrhetinic acid (GA) has been reported to be widely used as a targeting ligand to functionalize nanomaterials to treat hepatocellular carcinoma. In this article, GA is employed as a liver targeting ligand to construct GA, polyethylene glycol (PEG), polyamidoamine dendrimer (Dendrimer) and nano-graphene oxide (NGO) conjugate (GA-PEG-NGO-Dendrimer, GPND) for siRNA delivery for the first time. As we expected, GPND exhibited excellent stability, low toxicity, negligible hemolytic activity and remarkably high transfection efficiency in vitro. We also found effective VEGFa gene silencing in both mRNA and protein level in HepG2 cells. Notably, siRNA efficiently gathered in liver tumor tissues by the delivery of GPND, and eventually the growth of tumor tissues were inhibited with enhanced targeting capability and no obvious pathological changes. Moreover, histopathological results preliminarily support the high in vivo safety of GPND/anti-VEGFa siRNA nanocomplex. Collectively, GPND/siRNA nanocomplex, with high safety, targeting and transfection as well as prolonged half-life, is a promising nanomedicine and may provide a new direction for highly-specific targeted gene therapy.