Excessive friction and cellular senescence contribute to osteoarthritis (OA) development. However, synergistic treatments targeting these two causes of OA may have significant implications for OA. In this study, we propose a novel strategy for exosome delivery encapsulated an injectable and lubricated hydrogel to synchronously reduce the excessive friction and the accumulation of aged chondrocytes. A cartilage-targeting peptide HABP-PEG-COLBP was employed to achieve a stable and efficient lubrication. The zwitterions of phosphatidylcholine lipids secreted by the synovial membrane of the joint can adsorb water molecules, forming a hydrated layer around the charge. Moreover, the exosomes derived from bone marrow stem cell (BMSCs) were engineered with a chondrocyte affinity peptide (CAP) in the out membrane and si-STING in the exosome to reshape the senescence microenvironment. Furthemore, the in vivo data showed that the hydrogel/exosome delivery system successfully can alleviate the joint wear and rejuvenate chondrocytes to reverse the development of OA. The HD-T@CAP-Exos-siSTING gels can provide efficient lubrication and potentially alleviate friction-related diseases such as osteoarthritis. Teaser An injectable hydrogel delivering exosomes rejuvenates chondrocytes and reduces mechanical stress, presenting a potential osteoarthritis treatment strategy.
Ru-Yang Zhao,Mu-Zi Li,Qi-Qian Wang,Fu-Wei Jiang,Yi Zhao,Jin-Long Li
Butachlor (BTR), a globally prevalent amide herbicide, poses significant environmental health risks due to its bioaccumulation potential and documented chronic toxicity in mammalian systems. Given the spleen's pivotal role in orchestrating systemic immune homeostasis, this study investigated BTR-induced immunopathological mechanisms in ICR mice following 28-day subacute exposure (10 mg/kg). Histopathological examination revealed significant disorganization of the splenic marginal zone architecture, concomitant with ultrastructural mitochondrial abnormalities and a reduction in mitochondrial membrane potential (ΔΨm). Mitochondrial permeability transition pore opening triggered cytoplasmic translocation of mitochondrial DNA (mtDNA), activating the stimulator of interferon genes (STING) pathway—a master regulator of innate immunity. STING activation initiated bifurcated downstream signaling, evidenced by TBK1 phosphorylation and subsequent IRF3 / NF-κB nuclear translocation. This dual signaling cascade simultaneously executed immunogenic cell death via Gasdermin D-dependent pyroptosis (cleaved GSDMD-NT) and drove macrophage polarization (IFN-α / β, IL-1β, TNF-α). Crucially, pharmacological STING inhibition with C-176 attenuated both pyroptosis (GSDMD cleavage reduced) and inflammatory cytokine surge. Our findings not only pioneer the identification of the mtDNA-STING axis as the central mechanism underlying BTR-induced splenic immunotoxicity but also validate STING inactivation as a targeted strategy to mitigate herbicide-associated immune dysfunction. This work provides critical insights for environmental toxicant risk assessment and immunomodulatory.
Su Yanguo,Chen Rui,Wang Bingjie,Wang Teng,Tao Jiaojiao,Diao Qijie,Jiang Tianze,Zhao Xia
Activation of cGAS-STING signaling pathway and accumulation of reactive oxygen and nitrogen species (RONS) are important issues facing the treatment of rheumatoid arthritis (RA). Here, we report a biomimetic nano-Chinese medicine (HA-RM-Cel-BR) for RA immunotherapy based on STING inhibition of celastrol (Cel) and RONS clearance of bilirubin (BR). HA-RM-Cel-BR is constructed by the carrier-free self-assembly of active ingredients Cel and BR from traditional Chinese medicine, and then camouflaged by hyaluronic acid (HA)-modified red blood cell membranes (RM). HA-RM-Cel-BR prolongs circulation time through RM camouflage, targets inflamed joints by HA modification, and remodels the joint immune microenvironment by STING inhibition and RONS clearance. More importantly, HA-RM-Cel-BR shows excellent therapeutic effects on RA rat model, and significantly reduces hepatotoxicity associated with Cel. Our work provides a new strategy for RA immunotherapy with traditional Chinese medicine ingredients.
危险品化学品经营许可证（带存储）