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      Dual-engineered cartilage-targeting extracellular vesicles derived from mesenchymal stem cells enhance osteoarthritis treatment via miR-223/NLRP3/pyroptosis axis: Toward a precision therapy

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          Abstract

          Osteoarthritis (OA) is the most common disabling joint disease with no effective disease modifying drugs. Extracellular vesicles released by several types of mesenchymal stem cells could promote cartilage repair and ameliorate OA pathology in animal models, representing a novel therapeutic strategy. In this study, we demonstrated that extracellular vesicles derived from human umbilical cord mesenchymal stem cells (hUC-EVs) could maintain chondrocyte homeostasis and alleviate OA, and further revealed a novel molecular mechanism of this therapeutic effect. miR-223, which could directly bind with the 3′UTR of NLRP3 mRNA, was found to be a key miRNA for hUC-EVs to exert beneficial effects on inflammation inhibiting and cartilage protecting. For enhancing the effect on mitigating osteoarthritis, exogenous miR-223 was loaded into hUC-EVs by electroporation, and a collagen II-targeting peptide (WYRGRL) was modified onto the surface of hUC-EVs by genetic engineering to achieve a more targeted and efficient RNA delivery to the cartilage. The dual-engineered EVs showed a maximal effect on inhibiting the NLRP3 inflammasome activation and chondrocyte pyroptosis, and offered excellent results for the treatment of OA. This study provides a novel theoretical basis and a promising therapeutic strategy for the application of engineered extracellular vesicles in OA treatment.

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          • •

            HUC-EVs could maintain chondrocyte homeostasis and alleviate OA.

          • •

            MiR-223 directly targets NLRP3 to mediate the therapeutic effects of hUC-EVs.

          • •

            Dual-engineered hUC-EVs were obtained by miR-223 loading and surface modification.

          • •

            Dual-engineered hUC-EVs exhibit an amplified and excellent therapeutic effect for OA.

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          Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes.

          Lydia Alvarez-Erviti, Yiqi Seow, HaiFang Yin … (2011)
          To realize the therapeutic potential of RNA drugs, efficient, tissue-specific and nonimmunogenic delivery technologies must be developed. Here we show that exosomes-endogenous nano-vesicles that transport RNAs and proteins-can deliver short interfering (si)RNA to the brain in mice. To reduce immunogenicity, we used self-derived dendritic cells for exosome production. Targeting was achieved by engineering the dendritic cells to express Lamp2b, an exosomal membrane protein, fused to the neuron-specific RVG peptide. Purified exosomes were loaded with exogenous siRNA by electroporation. Intravenously injected RVG-targeted exosomes delivered GAPDH siRNA specifically to neurons, microglia, oligodendrocytes in the brain, resulting in a specific gene knockdown. Pre-exposure to RVG exosomes did not attenuate knockdown, and non-specific uptake in other tissues was not observed. The therapeutic potential of exosome-mediated siRNA delivery was demonstrated by the strong mRNA (60%) and protein (62%) knockdown of BACE1, a therapeutic target in Alzheimer's disease, in wild-type mice.
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            Exosomes Facilitate Therapeutic Targeting of Oncogenic Kras in Pancreatic Cancer

            Sushrut Kamerkar, Valerie LeBleu, Hikaru Sugimoto … (2017)
            Summary The mutant form of the GTPase KRAS is a key driver of pancreatic cancer but remains a challenging therapeutic target. Exosomes, extracellular vesicles generated by all cells, are naturally present in the blood. Here we demonstrate that enhanced retention of exosomes in circulation, compared to liposomes, is due to CD47 mediated protection of exosomes from phagocytosis by monocytes and macrophages. Exosomes derived from normal fibroblast-like mesenchymal cells were engineered to carry siRNA or shRNA specific to oncogenic KRASG12D (iExosomes), a common mutation in pancreatic cancer. Compared to liposomes, iExosomes target oncogenic Kras with an enhanced efficacy that is dependent on CD47, and is facilitated by macropinocytosis. iExosomes treatment suppressed cancer in multiple mouse models of pancreatic cancer and significantly increased their overall survival. Our results inform on a novel approach for direct and specific targeting of oncogenic Kras in tumors using iExosomes.
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              Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion

              Wan-ting He, Haoqiang Wan, Lichen Hu … (2015)
              Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of interleukin 1β (IL-1β) and IL-18 and triggers pyroptosis. Caspase-1 and -11 (or -4/5 in human) in the canonical and non-canonical inflammasome pathways, respectively, are crucial for inflammasome-mediated inflammatory responses. Here we report that gasdermin D (GSDMD) is another crucial component of inflammasomes. We discovered the presence of GSDMD protein in nigericin-induced NLRP3 inflammasomes by a quantitative mass spectrometry-based analysis. Gene deletion of GSDMD demonstrated that GSDMD is required for pyroptosis and for the secretion but not proteolytic maturation of IL-1β in both canonical and non-canonical inflammasome responses. It was known that GSDMD is a substrate of caspase-1 and we showed its cleavage at the predicted site during inflammasome activation and that this cleavage was required for pyroptosis and IL-1β secretion. Expression of the N-terminal proteolytic fragment of GSDMD can trigger cell death and N-terminal modification such as tagging with Flag sequence disrupted the function of GSDMD. We also found that pro-caspase-1 is capable of processing GSDMD and ASC is not essential for GSDMD to function. Further analyses of LPS plus nigericin- or Salmonella typhimurium-treated macrophage cell lines and primary cells showed that apoptosis became apparent in Gsdmd −/− cells, indicating a suppression of apoptosis by pyroptosis. The induction of apoptosis required NLRP3 or other inflammasome receptors and ASC, and caspase-1 may partially contribute to the activation of apoptotic caspases in Gsdmd −/− cells. These data provide new insights into the molecular mechanisms of pyroptosis and reveal an unexpected interplay between apoptosis and pyroptosis.
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                Author and article information

                Contributors
                Hao Xiong
                Shiyang Yu
                Xintao Zhang
                Cunyi Fan
                Journal
                Journal ID (nlm-ta): Bioact Mater
                Journal ID (iso-abbrev): Bioact Mater
                Title: Bioactive Materials
                Publisher: KeAi Publishing
                ISSN (Electronic): 2452-199X
                Publication date PMC-release: 04 August 2023
                Publication date Collection: December 2023
                Publication date (Electronic): 04 August 2023
                Volume: 30
                Pages: 169-183
                Affiliations
                [a ]Department of Sports Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China
                [b ]Shanghai Engineering Research Center for Orthopedic Material Innovation and Tissue Regeneration, Shanghai, 201306, China
                [c ]Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
                [d ]Department of Orthodontics, Shanghai Stomatological Hospital & School of Stomatology, Fudan University, Shanghai, 200001, China
                [e ]Shanghai Key Laboratory of Craniomaxillofacial Development and Diseases, Fudan University, Shanghai, 200001, China
                [f ]Minhang Hospital, Fudan University, Shanghai, 201199, China
                Author notes
                [∗ ]Corresponding author. Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. cyfan@ 123456sjtu.edu.cn
                [∗∗ ]Corresponding author. Department of Sports Medicine, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology Medical Center, Shenzhen, 518036, China. zhangxintao@ 123456sina.com
                [∗∗∗ ]Corresponding author. Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. yushiyangysy@ 123456126.com
                [∗∗∗∗ ]Corresponding author. Department of Orthopedics, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China. 15870679103@ 123456163.com
                [1]

                These authors contributed equally to this work.

                Article
                Publisher Item ID: S2452-199X(23)00195-0
                DOI: 10.1016/j.bioactmat.2023.06.012
                PMC ID: 10429745
                PubMed ID: 37593145
                SO-VID: d00254ed-75a4-44d3-9ead-2b2def0983eb
                Copyright © © 2023 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 22 November 2022
                Date revision received : 24 May 2023
                Date accepted : 19 June 2023
                Categories
                Subject: Article

                Keywords: osteoarthritis,extracellular vesicles,nlrp3 inflammasome,pyroptosis,cartilage-targeting
                Data availability:
                Keywords: osteoarthritis, extracellular vesicles, nlrp3 inflammasome, pyroptosis, cartilage-targeting

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