Yinghua Peng

Intramuscular fat (IMF) deposition is a critical determinant of beef quality, yet the regulatory role of preadipocyte-derived exosomes remains unclear. Exosomes (HC-Exo and CRSC-Exo) were isolated from preadipocytes of Haoyue Beef Cattle (HC) and Chinese Red Steppe Cattle (CRSC), breeds with distinct IMF contents. HC-Exo significantly enhanced preadipocyte proliferation and differentiation, increasing lipid droplet formation and triglyceride synthesis, alongside elevated expression levels of peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT enhancer binding protein alpha (C/EBPα). MiRNA sequencing identified 580 differentially expressed miRNAs, with miR-26a twice as abundant in HC-Exo versus CRSC-Exo. Integrated bioinformatics analyses, including KEGG, GO, and dual-luciferase reporter assays, identified glycogen synthase kinase-3B (GSK3B) as a direct target of miR-26a. Functional validation demonstrated that miR-26a mimics enhanced adipogenesis by suppressing GSK3B expression, while GSK3B overexpression inhibited differentiation. These findings establish exosomal miR-26a as a novel regulator of intramuscular adipogenesis, providing molecular insights for improving beef quality.

Cuproptosis-based immunotherapy shows significant potential in the treatment of cancer. However, its therapeutic effectiveness is hampered by inefficient copper delivery, poor targeting, tumor metabolic reprogramming, and the immunosuppressive tumor microenvironment. Herein, a self-carrier nanoagonist was constructed to achieve positive feedback regulation of cuproptosis-immunity for potent antitumor therapy. The nanoagonist, as a cuproptosis inducer assembled from nucleotides and copper ions, resulted in mitochondrial damage and mitochondrial DNA (mtDNA) release, thereby promoting immunogenic cell death (ICD) and stimulator of interferon gene (STING) activation. Notably, the metal-coordination-driven nanoagonist also functioned as a mimic of the natural STING agonist 2',3'-cyclic GMP-AMP (2',3'-cGAMP), directly stimulating the STING pathway. Density functional theory calculations were performed to elucidate the geometry of the nanoagonist, while dynamic molecular docking analyses demonstrated a high binding affinity between the nanoagonist and STING. In turn, STING activation, combined with 2-deoxy-d-glucose, modulated tumor cell metabolic pathways by blocking glycolysis to alleviate tumor cell tolerance to copper and sensitize cuproptosis, further inducing ICD and amplifying the STING signal. In vivo experiments demonstrated that the reciprocal amplification between cuproptosis and the STING pathway remodeled the immune microenvironment and enhanced the efficacy of antitumor immunotherapy. The work offers a promising strategy to potentiate the cancer-immunity cycle and improve immunotherapy outcomes.

Taraxacum mongolicum Hand.-Mazz. derived extracellular vesicles alleviate mastitis via NLRP3 inflammasome and NF-κB/MAPK pathways, highlighting TH-EVs as a natural and potent nanotherapeutic agent for mastitis treatment.

The cyclic GMP-AMP synthase (cGAS)/stimulator of interferon gene (STING) pathway can respond to double-stranded DNA (dsDNA) to mediate innate immunity. However, activation of the cGAS/STING pathway initiates autophagy, which typically plays a negative regulatory role in the cGAS-STING pathway, largely attenuating the efficacy of antitumor immunity. Herein, we construct an oligonucleotide-based bioorthogonal platform to intervene in the crosstalk between the cGAS-STING pathway and autophagy, thereby achieving enhanced immunotherapy. In the platform, a dsDNA segment conjugated with unpaired guanosines serves as an agonist for the cGAS-STING pathway. The i-motif acts as a template for synthesizing palladium nanoparticles, which catalyze the synthesis of autophagy inhibitor and also function as carriers of oligonucleotides. Furthermore, the platform includes an aptamer for targeted delivery to cancer cells. In cancer cells, the platform activates the cGAS-STING pathway and disrupts autophagy, enhancing the anticancer immunity. This study provides a promising strategy to improve outcomes in tumor immunotherapy.

Cannabidiol (CBD), a phytocannabinoid from Cannabis sativa, is renowned for its nonpsychoactive properties and therapeutic potential. However, its clinical application is limited by nonselective cytotoxicity, affecting microglia, oligodendrocytes, and other cells. To address this, subcellular organelle-targeting strategies were explored to minimize off-target effects and enhance CBD's therapeutic index. Three organelle-specific conjugates targeting mitochondria, endoplasmic reticulum, and lysosomes were synthesized. Among these, the mitochondria-targeting triphenylphosphonium (TPP)-modified CBD conjugates demonstrated reduced cytotoxicity and enhanced anti-inflammatory activity. Further optimization identified a four-carbon ether chain linker (CBD-TPP-C4) that increased antineuroinflammatory activity by 3-fold and reduced cytotoxicity by 1.6-fold, compared to unmodified CBD. CBD-TPP-C4 also elevated mitochondrial ATP levels in vitro, improved mitochondrial morphology and locomotor function in Caenorhabditis elegans, and potentiated morphine analgesia in mice. These findings highlight subcellular targeting as a promising strategy to enhance CBD's safety and efficacy, paving the way for improved therapeutic applications.

Despite the approval of several artificial nanotherapeutics for the treatment of triple-negative breast cancer (TNBC), significant challenges, including unsatisfactory therapeutic outcomes, severe side effects, and the high cost of large-scale production, still restrict their long-term application. In contrast, plant-derived extracellular vesicles (PEVs) exhibit promising potential in cancer therapy due to their negligible systemic toxicity, high bioavailability and cost- effectiveness. In this study, we developed an alternative strategy to inhibit TNBC via Platycodon grandiflorum (PG)-derived extracellular vesicles (PGEVs). The PGEVs were isolated by ultracentrifugation and sucrose gradient centrifugation method and contained adequate functional components such as proteins, lipids, RNAs and active molecules. PGEVs exhibited remarkable stability, tolerating acidic digestion and undergoing minimal changes in simulated gastrointestinal fluid. They were efficiently taken up by tumor cells and induced increased production of reactive oxygen species (ROS), leading to tumor cell proliferation inhibition and apoptosis, particularly in the TNBC cell line 4T1. Additionally, PGEVs facilitated the polarization of tumor-associated macrophages (TAMs) toward M1 phenotype and increased the secretion of pro-inflammatory cytokines. Further in vivo investigations revealed that PGEVs efficiently accumulated in 4T1 tumors and exerted significant therapeutic effects through boosting systemic anti-tumor immune responses and modulating the gut microbiota whether administered orally or intravenously (i.v.). In conclusion, these findings highlight PGEVs as a promising natural, biocompatible and efficient nanotherapeutic candidate for treating TNBC.

Ginsenosides possess potential protective effects against cisplatin (CDDP)-induced toxicity, but the limited bioavailability of ginsenosides hampered their therapeutic application. Ginseng exosomes (G-Exo), which are active ingredients in ginseng, exhibit excellent biocompatibility and low immunogenicity. Here, G-Exo were isolated from ginseng roots through a combination of ultracentrifugation and sucrose gradient centrifugation techniques. Subsequently, the potential protective effect of G-Exo on CDDP induced cardiotoxicity, and its underlying mechanisms were explored. The findings demonstrated that G-Exo effectively mitigated CDDP-induced oxidative stress and apoptosis in vitro. Moreover, in vivo experiments revealed that G-Exo significantly inhibited the increases in serum cardiac troponin T (cTnT), creatine kinase (CK), and lactate dehydrogenase (LDH) levels in mice induced by CDDP. Histological assessment and tissue staining further corroborated that G-Exo alleviated the cardiac tissue damage and apoptosis caused by CDDP. Mechanistically, G-Exo were found to alleviate CDDP-induced apoptosis through blocking the MAPK signaling. Collectively, these results suggest that G-Exo hold the potential to mitigate cisplatin-induced cardiac injury by regulating the MAPK pathway, thereby highlighting the therapeutic potential of G-Exo as a protective agent against CDDP-induced cardiotoxicity.

Background: Deer antlers, unique among mammalian organs for their ability to regenerate annually without scar formation, provide an innovative model for regenerative medicine. This study explored the potential of exosomes derived from antler mesenchymal stem cells (AMSC-Exo) to enhance skin wound healing. Methods: We explored the proliferation, migration and angiogenesis effects of AMSC-Exo on HaCaT cells and HUVEC cells. To investigate the skin repairing effect of AMSC-Exo, we established a full-thickness skin injury mouse model. Then the skin thickness, the epidermis, collagen fibers, CD31 and collagen expressions were tested by H&E staining, Masson’s trichrome staining and immunofluorescence experiments. MiRNA omics analysis was conducted to explore the mechanism of AMSC-Exo in skin repairing. Results: AMSC-Exo stimulated the proliferation and migration of HaCaT cells, accelerated the migration and angiogenesis of HUVEC cells. In the mouse skin injury model, AMSC-Exo stimulated angiogenesis and regulated the extracellular matrix by facilitating the conversion of collagen type III to collagen type I, restoring epidermal thickness to normal state without aberrant hyperplasia. Notably, AMSC-Exo enhanced the quality of wound healing with increased vascularization and reduced scar formation. MiRNAs in AMSC-Exo, especially through the miR-21-5p/STAT3 signaling pathway, played a crucial role in these processes. Conclusion: This study underscores the efficacy of AMSC-Exo in treating skin wounds, suggesting a new approach for enhancing skin repair and regeneration.