Synthesis and Characterization of Copper-Crosslinked Carbon Dot Nanoassemblies for Efficient Macrophage Manipulation.

Nanomedicines loaded in macrophages (MAs) can actively target tumors without dominantly relying on the enhanced permeability and retention (EPR) effect, making them effective for treating EPR-deficient malignancies. Herein, copper-crosslinked carbon dot clusters (CDCs) are synthesized with both photodynamic and chemodynamic functions to manipulate MAs, aiming to direct the MA-mediated tumor targeting. First, green fluorescent CDs (g-CDs) are prepared by a one-step hydrothermal method. Subsequently, the g-CDs are complexed with divalent copper ions to form copper-crosslinked CDCs (g-CDCs/Cu), which are incubated with MAs for their manipulation. Experimental results revealed that the prepared g-CDCs/Cu displayed good aqueous dispersibility and fluorescent emission properties. The nanoassemblies can be activated to deplete the overexpressed glutathione (GSH) and generate reactive oxygen species (ROS) in the presence of laser irradiation through the combined Cu-mediated chemodynamic therapy and CD-mediated photodynamic therapy. Furthermore, the ROS produced in MAs enabled polarization of MAs to antitumor M1 phenotype, suggesting the future potential use to reverse the immunosuppressive tumor microenvironment. These results obtained from the current study suggest a significant potential to develop g-CDCs/Cu for GSH depletion, ROS generation, and MA M1 polarization as a theransotic agent to tackle cancer.

Targeted nanoparticles triggered by plaque microenvironment for atherosclerosis treatment through cascade effects of reactive oxygen species scavenging and anti-inflammation.

Inflammatory factors and reactive oxygen species (ROS) are risk factors for atherosclerosis. Many existing therapies use ROS-sensitive delivery systems to alleviate atherosclerosis, which achieved certain efficacy, but cannot eliminate excessive ROS. Moreover, the potential biological safety concerns of carrier materials through chemical synthesis cannot be ignored. Herein, an amphiphilic low molecular weight heparin- lipoic acid conjugate (LMWH-LA) was used as a ROS-sensitive carrier material, which consisted of injectable drug molecules used clinically, avoiding unknown side effects. LMWH-LA and curcumin (Cur) self-assembled to form LLC nanoparticles (LLC NPs) with LMWH as shell and LA/Cur as core, in which LMWH could target P-selectin on plaque endothelial cells and competitively block the migration of monocytes to endothelial cells to inhibit the origin of ROS and inflammatory factors, and LA could be oxidized to trigger hydrophilic-hydrophobic transformation and accelerate the release of Cur. Cur released within plaques further exerted anti-inflammatory and antioxidant effects, thereby suppressing ROS and inflammatory factors. We used ultrasound imaging, pathology and serum analysis to evaluate the therapeutic effect of nanoparticles on atherosclerotic plaques in apoe-/- mice, and the results showed that LLC showed significant anti-atherosclerotic effects. Our finding provided a promising therapeutic nanomedicine for the treatment of atherosclerosis.

Three-dimensional porous gas-foamed electrospun nanofiber scaffold for cartilage regeneration.

To achieve optimal functional recovery of articular cartilage, scaffolds with nanofibrous structure and biological function have been widely pursued. In this study, two-dimensional electrospun poly(l-lactide-co-ε-caprolactone)/silk fibroin (PLCL/SF) scaffolds (2DS) were fabricated by dynamic liquid support (DLS) electrospinning system, and then cross-linked with hyaluronic acid (HA) to further mimic the microarchitecture of native cartilage. Subsequently, three-dimensional PLCL/SF scaffolds (3DS) and HA-crosslinked three-dimensional scaffolds (3DHAS) were successfully fabricated by in situ gas foaming and freeze-drying. 3DHAS exhibited better mechanical properties than that of the 3DS. Moreover, all scaffolds exhibited excellent biocompatibility in vitro. 3DHAS showed better proliferation and phenotypic maintenance of chondrocytes as compared to the other scaffolds. Histological analysis of cell-scaffold constructs explanted 8 weeks after implantation demonstrated that both 3DS and 3DHAS scaffolds formed cartilage-like tissues, and the cartilage lacuna formed in 3DHAS scaffolds was more mature. Moreover, the reparative capacity of scaffolds was discerned after implantation in the full-thickness articular cartilage model in rabbits for up to 12 weeks. The macroscopic and histological results exhibited typical cartilage-like character and well-integrated boundary between 3DHAS scaffolds and the host tissues. Collectively, biomimetic 3DHAS scaffolds may be promising candidates for cartilage tissue regeneration applications.

Gas foaming of electrospun poly(L-lactide-co-caprolactone)/silk fibroin nanofiber scaffolds to promote cellular infiltration and tissue regeneration.

Electrospun nanofibers emulate extracellular matrix (ECM) morphology and architecture; however, small pore size and tightly-packed fibers impede their translation in tissue engineering. Here we exploited in situ gas foaming to afford three-dimensional (3D) poly(L-lactide-co-ε-caprolactone)/silk fibroin (PLCL/SF) scaffolds, which exhibited nanotopographic cues and a multilayered structure. The addition of SF improved the hydrophilicity and biocompatibility of 3D PLCL scaffolds. Three-dimensional scaffolds exhibited larger pore size (38.75 ± 9.78 µm2) and high porosity (87.1% ± 1.5%) than that of their 2D counterparts. 3D scaffolds also improved the deposition of ECM components and neo-vessel regeneration as well as exhibited more numbers of CD163+/CCR7+ cells after 2 weeks implantation in a subcutaneous model. Collectively, 3D PLCL/SF scaffolds have broad implications for regenerative medicine and tissue engineering applications.