An Antioxidative and Active Shrinkage Hydrogel Integratedly Promotes Re-Epithelization and Skin Constriction for Enhancing Wound Closure.

Delayed re-epithelization and weakened skin contractions are the two primary factors that hinder wound closure in large-scale acute or chronic wounds. However, effective strategies for targeting these two aspects concurrently are still lacking. Herein, an antioxidative active-shrinkage hydrogel (AHF@AS Gel) is constructed that can integratedly promote re-epithelization and skin constriction to accelerate large-scale acute and diabetic chronic wound closure. The AHF@AS Gel is encapsulated by antioxidative amino- and hydroxyl-modified C70 fullerene (AHF) and a thermosensitive active shrinkage hydrogel (AS Gel). Specifically, AHF relieves overactivated inflammation, prevents cellular apoptosis, and promotes fibroblast migration in vitro by reducing excessive reactive oxygen species (ROS). Notably, the AHF@AS Gel achieved ≈2.7-fold and ≈1.7-fold better re-epithelization in acute wounds and chronic diabetic wounds, respectively, significantly contributing to the promotion of wound closure. Using proteomic profiling and mechanistic studies, it is identified that the AHF@AS Gel efficiently promoted the transition of the inflammatory and proliferative phases to the remodeling phase. Notably, it is demonstrated that AS Gel alone activates the mechanosensitive epidermal growth factor receptor/Akt (EGFR/Akt) pathway and promotes cell proliferation. The antioxidative active shrinkage hydrogel offers a comprehensive strategy for acute wound and diabetic chronic wound closure via biochemistry regulation integrating with mechanical forces stimulation.

Curdlan-Decorated Fullerenes Mitigate Immune-Mediated Hepatic Injury for Autoimmune Hepatitis Therapeutics via Reducing Macrophage Infiltration.

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease whose standard of care is immunosuppressive treatment with inevitable undesired outcomes. Macrophage is acknowledged to aggravate liver damage, providing a promising AIH therapeutic target. Accordingly, in this study, a kind of curdlan-decorated fullerene nanoparticle (Cur-F) is fabricated to alleviate immune-mediated hepatic injury for treating AIH via reducing macrophage infiltration in a concanavalin A (Con A)-induced AIH mouse model. After intravenous administration, Cur-F primarily distributes in liver tissues, efficiently eliminates the excessive reactive oxygen species, significantly attenuates oxidative stress, and subsequently suppresses the nuclear factor kappa-B-gene binding (NF-κB) signal pathway, resulting in the lowered production of pro-inflammatory cytokines and the balancing of the immune homeostasis with the prevention of macrophage infiltration in the liver. The regulation of hepatic inflammation contributes to inhibiting inflammatory cytokines-induced hepatocyte apoptosis, decreasing the serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) contents and thus ameliorating immune-mediated hepatic injury. Notably, there is no detectable toxicity to the body. Our findings may open up novel avenues for AIH based on curdlan and fullerene materials.

Oral nano-antioxidants improve sleep by restoring intestinal barrier integrity and preventing systemic inflammation.

Sleep deprivation (SD) is a severe public health threat that can cause systemic inflammation and nerve damage. Few effective and side-effect-free drugs are available to address SD. However, the bidirectional communications between the brain and gut provide new strategies for anti-SD therapeutics. Here we explored oral delivery of fullerene nano-antioxidants (FNAO) in the SD model to improve sleep by regulating abnormal intestinal barrier and systemic inflammation via the brain-gut axis. SD caused excessive reactive oxygen species (ROS) production and hyperactive inflammatory responses in the intestines of zebrafish and mouse models, leading to disturbed sleep patterns and reduced brain nerve activity. Of note, based on the property of the conjugated π bond of the C60 structure to absorb unpaired electrons, oral FNAO efficiently reduced the excessive ROS in the intestines, maintained redox homeostasis and intestinal barrier integrity, and ameliorated intestinal and systemic inflammation, resulting in superior sleep improvement. Our findings suggest that maintaining intestinal homeostasis may be a promising avenue for SD-related nerve injury therapy.

Dynamic assembly of DNA-ceria nanocomplex in living cells generates artificial peroxisome.

Intracellular accumulation of reactive oxygen species (ROS) leads to oxidative stress, which is closely associated with many diseases. Introducing artificial organelles to ROS-imbalanced cells is a promising solution, but this route requires nanoscale particles for efficient cell uptake and micro-scale particles for long-term cell retention, which meets a dilemma. Herein, we report a deoxyribonucleic acid (DNA)-ceria nanocomplex-based dynamic assembly system to realize the intracellular in-situ construction of artificial peroxisomes (AP). The DNA-ceria nanocomplex is synthesized from branched DNA with i-motif structure that responds to the acidic lysosomal environment, triggering transformation from the nanoscale into bulk-scale AP. The initial nanoscale of the nanocomplex facilitates cellular uptake, and the bulk-scale of AP supports cellular retention. AP exhibits enzyme-like catalysis activities, serving as ROS eliminator, scavenging ROS by decomposing H2O2 into O2 and H2O. In living cells, AP efficiently regulates intracellular ROS level and resists GSH consumption, preventing cells from redox dyshomeostasis. With the protection of AP, cytoskeleton integrity, mitochondrial membrane potential, calcium concentration and ATPase activity are maintained under oxidative stress, and thus the energy of cell migration is preserved. As a result, AP inhibits cell apoptosis, reducing cell mortality through ROS elimination.

A DNA Nanocomplex Containing Cascade DNAzymes and Promoter-Like Zn-Mn-Ferrite for Combined Gene/Chemo-dynamic Therapy.

Sequential control of exogenous chemical events inside cells is a promising way to regulate cell functions and fate. Herein we report a DNA nanocomplex containing cascade DNAzymes and promoter-like Zn-Mn-Ferrite (ZMF), achieving combined gene/chemo-dynamic therapy. The promoter-like ZMF decomposed in response to intratumoral glutathione to release a sufficient quantity of metal ions, thus promoting cascade DNA/RNA cleavage and free radical generation. Two kinds of DNAzymes were designed for sequential cascade enzymatic reaction, in which metal ions functioned as cofactors. The primary DNAzyme self-cleaved the DNA chain with Zn2+ as cofactor, and produced the secondary DNAzyme; the secondary DNAzyme afterwards cleaved the EGR-1 mRNA, and thus downregulated the expression of target EGR-1 protein, achieving DNAzyme-based gene therapy. Meanwhile, the released Zn2+ , Mn2+ and Fe2+ induced Fenton/Fenton-like reactions, during which free radicals were catalytically generated and efficient chemo-dynamic therapy was achieved. In a breast cancer mouse model, the administration of DNA nanocomplex led to a significant therapeutic efficacy of tumor growth suppression.