Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis

Advanced Science, Год журнала: 2023, Номер 10(11)

Опубликована: Фев. 7, 2023

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, its progression closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for regulation of intracellular/extracellular nitric oxide (NO) hydrogen protons reprogramming macrophages proposed. The combination carbonic anhydrase IX (CA9) siRNA NO scavenger "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) developed OA therapy scavenging inhibiting CA9 expression In vitro experiments demonstrate that these NPs can significantly scavenge intracellular similar levels as those normal group downregulate mRNA (≈90%), thereby repolarizing M1 into M2 phenotype increasing pro-chondrogenic TGF-β1 (≈1.3-fold), chondrocyte apoptosis. Furthermore, vivo show have great anti-inflammation, protection repair effects, effectively alleviating both monoiodoacetic acid-induced early late mouse models surgical destabilization medial meniscus-induced rat model. Therefore, siCA9 delivery system potential efficient treatment.

Язык: Английский

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Functionalized DNA Nanomaterials Targeting Toll‐Like Receptor 4 Prevent Bisphosphonate‐Related Osteonecrosis of the Jaw via Regulating Mitochondrial Homeostasis in Macrophages

Advanced Functional Materials, Год журнала: 2023, Номер 33(15)

Опубликована: Янв. 27, 2023

Abstract Imbalance of macrophage polarization characterized by an increase in the percentage pro‐inflammatory M1 macrophages and a decrease anti‐inflammatory M2 is considered critical pathogenic mechanism bisphosphonate‐related osteonecrosis jaws (BRONJ). Because high levels Toll‐like receptor 4 (TLR4) mediates mitochondrial dyshomeostasis Zoledronic Acid (ZA)‐treated macrophages, tetrahedral DNA nanomaterial (TDN)‐modified with TLR4‐siRNA on each vertex (TDN‐TLR4‐4siR) excellent biocompatibility synthesized. This novel TDN‐TLR4‐4siR reverses phenotype imbalance decreasing RAW264.7 macrophages. Mitochondrial dynamics analysis shows shift from short rod‐like ultrastructure to elongated shapes more network continuity ZA‐primed after treatment TDN‐TLR4‐4siR, along elevated expression Mfn1 Mfn2 . further reduces intracellular ROS production restored membrane potential. Furthermore, decreased sequestra formation accelerated healing extraction wound are observed group, resulting incidence rat BRONJ via reprogramming polarized Consequently, this study establishes strategy using regulate homeostasis prevent BRONJ.

Язык: Английский

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Reprogramming macrophages via immune cell mobilized hydrogel microspheres for osteoarthritis treatments

Bioactive Materials, Год журнала: 2023, Номер 32, С. 242 - 259

Опубликована: Окт. 12, 2023

Regulating macrophage activation precisely is crucial in treating chronic inflammation osteoarthritis (OA). However, the stable pro-inflammatory state and deep distribution of macrophages vivo pose a great challenge to treatment. In this study, inspired by innate immune, immune cell mobilized hydrogel microspheres were constructed microfluidic methods load chemokines, antibodies engineered membrane vesicles (sEVs) via covalent non-covalent junctions. The microspheres, based on mixture streptavidin grafted hyaluronic acid methacrylate (HAMA-SA) Chondroitin sulfate (ChSMA) (HCM), can recruit, capture reprogram proinflammatory joint cavity improve inflammatory microenvironment. vitro experiments demonstrated that had excellent recruitment, capture, reprogramming abilities. Pro-inflammatory be transformed into anti-inflammatory with an efficiency 88.5 %. Animal also revealed significant reduction synovial cartilage matrix degradation OA. Therefore, may effective treatment OA for future.

Язык: Английский

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Using Cu‐Based Metal–Organic Framework as a Comprehensive and Powerful Antioxidant Nanozyme for Efficient Osteoarthritis Treatment

Advanced Science, Год журнала: 2024, Номер 11(13)

Опубликована: Янв. 26, 2024

Abstract Developing nanozymes with effective reactive oxygen species (ROS) scavenging ability is a promising approach for osteoarthritis (OA) treatment. Nonetheless, numerous lie in their relatively low antioxidant activity. In certain circumstances, some of these may even instigate ROS production to cause side effects. To address challenges, copper‐based metal–organic framework (Cu MOF) nanozyme designed and applied OA Cu MOF exhibits comprehensive powerful activities (i.e., SOD‐like, CAT‐like, •OH activities) while negligible pro‐oxidant (POD‐ OXD‐like activities). Collectively, more at various types than other Cu‐based antioxidants, such as commercial CuO single‐atom nanozyme. Density functional theory calculations also confirm the origin its outstanding enzyme‐like activities. vitro vivo results demonstrate that an excellent decrease intracellular levels relieve hypoxic microenvironment synovial macrophages. As result, can modulate polarization macrophages from pro‐inflammatory M1 anti‐inflammatory M2 subtype, inhibit degradation cartilage matrix efficient The biocompatibility protective properties make it valuable asset treating ROS‐related ailments beyond OA.

Язык: Английский

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Reprogramming of Mitochondrial Respiratory Chain Complex by Targeting SIRT3‐COX4I2 Axis Attenuates Osteoarthritis Progression

Advanced Science, Год журнала: 2023, Номер 10(10)

Опубликована: Янв. 22, 2023

Mitochondrial homeostasis is of great importance for cartilage integrity and associated with the progression osteoarthritis (OA); however, underlying mechanisms are unknown. This study aims to investigate role mitochondrial deacetylation reaction mechanistic relationship OA development. Silent mating type information regulation 2 homolog 3 (SIRT3) expression has a negative correlation severity in both human arthritic mice inflammatory chondrocytes. Global SIRT3 deletion accelerates pathological phenotype post-traumatic mice, as evidenced by extracellular matrix collapse, osteophyte formation, synovial macrophage M1 polarization. Mechanistically, prevents targeting deacetylating cytochrome c oxidase subunit 4 isoform (COX4I2) maintain at post-translational level. The activation honokiol restores metabolic equilibrium protects from development OA. Collectively, loss essential OA, whereas SIRT3-mediated proteins COX4I2 rescues OA-impaired respiratory chain functions improve phenotype. Herein, induction provides novel therapeutic candidate treatment.

Язык: Английский

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Reprogramming Macrophage Polarization, Depleting ROS by Astaxanthin and Thioketal‐Containing Polymers Delivering Rapamycin for Osteoarthritis Treatment

Advanced Science, Год журнала: 2023, Номер 11(9)

Опубликована: Дек. 14, 2023

Abstract Osteoarthritis (OA) is a chronic joint disease characterized by synovitis and cartilage destruction. The severity of OA highly associated with the imbalance between M1 M2 synovial macrophages. In this study, novel strategy designed to modulate macrophage polarization reducing intracellular reactive oxygen species (ROS) levels regulating mitochondrial function. A ROS‐responsive polymer synthesized self‐assemble astaxanthin autophagy activator rapamycin form nanoparticles (NP@Poly RHAPM ). vitro experiments show that NP@Poly significantly reduced ROS levels. Furthermore, restored membrane potential, increased glutathione (GSH) levels, promoted autophagy, hence successfully repolarizing macrophages into phenotype. This repolarization enhanced chondrocyte proliferation vitality while inhibiting apoptosis. vivo utilizing an anterior cruciate ligament transection (ACLT)‐induced mouse model revealed anti‐inflammatory cartilage‐protective effects , effectively mitigating progression. Consequently, findings suggest intra‐articular delivery nanocarrier systems holds significant promise as potential effective therapeutic for treatment.

Язык: Английский

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Targeting macrophage polarization as a promising therapeutic strategy for the treatment of osteoarthritis

International Immunopharmacology, Год журнала: 2023, Номер 116, С. 109790 - 109790

Опубликована: Фев. 1, 2023

Язык: Английский

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Inflammatory Fibroblast‐Like Synoviocyte‐Derived Exosomes Aggravate Osteoarthritis via Enhancing Macrophage Glycolysis

Advanced Science, Год журнала: 2024, Номер 11(14)

Опубликована: Фев. 11, 2024

Abstract The severity of osteoarthritis (OA) and cartilage degeneration is highly associated with synovial inflammation. Although recent investigations have revealed a dysregulated crosstalk between fibroblast‐like synoviocytes (FLSs) macrophages in the pathogenesis synovitis, limited knowledge available regarding involvement exosomes. Here, increased exosome secretion observed FLSs from OA patients. Notably, internalization inflammatory FLS‐derived exosomes (inf‐exo) can enhance M1 polarization macrophages, which further induces an OA‐like phenotype co‐cultured chondrocytes. Intra‐articular injection inf‐exo synovitis exacerbates progression murine models. In addition, it demonstrated that stimulation triggers activation glycolysis. Inhibition glycolysis using 2‐DG successfully attenuates excessive triggered by inf‐exo. Mechanistically, HIF1A identified as determinant transcription factor, inhibition which, both pharmacologically or genetically, relieves macrophage inflammation inf‐exo‐induced hyperglycolysis. Furthermore, vivo administration inhibitor alleviates experimental OA. results provide novel insights into pathogenesis, suggesting dysfunction represents attractive target for therapy.

Язык: Английский

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Revitalizing Ancient Mitochondria with Nano‐Strategies: Mitochondria‐Remedying Nanodrugs Concentrate on Disease Control

Advanced Materials, Год журнала: 2024, Номер 36(18)

Опубликована: Янв. 15, 2024

Abstract Mitochondria, widely known as the energy factories of eukaryotic cells, have a myriad vital functions across diverse cellular processes. Dysfunctions within mitochondria serve catalysts for various diseases, prompting widespread demise. Mounting research on remedying damaged indicates that constitute valuable target therapeutic intervention against diseases. But less clinical practice and lower recovery rate imply limitation traditional drugs, which need further breakthrough. Nanotechnology has approached favorable regiospecific biodistribution high efficacy by capitalizing excellent nanomaterials targeting drug delivery. Mitochondria‐remedying nanodrugs achieved ideal effects. This review elucidates significance in cells organs, while also compiling mortality data related Correspondingly, nanodrug‐mediate strategies applicable mitochondria‐remedying disease are detailed, with full understanding roles dysfunction advantages nanodrugs. In addition, future challenges directions discussed. conclusion, this provides comprehensive insights into design development nanodrugs, aiming to help scientists who desire extend their fields engage interdisciplinary subject.

Язык: Английский

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Self‐Reinforced MOF‐Based Nanogel Alleviates Osteoarthritis by Long‐Acting Drug Release

Advanced Materials, Год журнала: 2024, Номер unknown

Опубликована: Апрель 29, 2024

Abstract Intra‐articular injection of drugs is an effective strategy for osteoarthritis (OA) treatment. However, the complex microenvironment and limited joint space result in rapid clearance drugs. Herein, a nanogel‐based proposed prolonged drug delivery remodeling. Nanogel constructed through functionalization hyaluronic acid (HA) by amide reaction on surface Kartogenin (KGN)‐loaded zeolitic imidazolate framework‐8 (denoted as KZIF@HA). Leveraging inherent hydrophilicity HA, KZIF@HA spontaneously forms nanogels, ensuring extended release OA microenvironment. exhibits sustained over one month, with low leakage risk from cavity compared to KZIF, enhanced cartilage penetration, reparative effects chondrocytes. Notably, KGN released serves promote extracellular matrix (ECM) secretion hyaline regeneration. Zn 2+ reverses progression promoting M2 macrophage polarization establish anti‐inflammatory Ultimately, facilitates regeneration alleviation within three months. Transcriptome sequencing validates that stimulates macrophages secretes IL‐10 inhibit JNK ERK pathways, chondrocytes recovery enhancing ECM This pioneering nanogel system offers new therapeutic opportunities release, presenting significant stride treatment strategies.

Язык: Английский

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