Augmenting Intracellular Cargo Delivery of Extracellular Vesicles in Hypoxic Tissues through Inhibiting Hypoxia-Induced Endocytic Recycling

Tong, Bide; Liao, Zhiwei; Liu, Hui; Ke, Wencan; Lei, Chunchi; Zhang, Weifeng; Liang, Huaizhen; Wang, Hongchuan; He, Yaqi; Lei, Jie; Yang, Kaiwen; Zhang, Xiaoguang; Li, Gaocai; Ma, Liang; Song, Yu; Hua, Wenbin; Feng, Xiaobo; Wang, Kun; Wu, Xinghuo; Liu, Tan; Gao, Yong; Yang, Cao

doi:10.1021/acsnano.2c10351

Cited by 14 publications

(5 citation statements)

References 53 publications

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“…Oxygen sensing pathway was found to regulate endocytosis 38 . Previous studies have also demonstrated that intracellular cargo delivery of exosomes is undermined in hypoxic tissues 18 . Therefore, EBO is expected to restore exosome delivery efficiency in hypoxic microenvironments by supplying oxygen.…”

Section: Resultsmentioning

confidence: 99%

“…Notably, exosomes offer several advantages over stem cells, as they are considered safer, lack tumorigenic potential, and pose a minimal risk of embolism 16 , 17 . Nevertheless, recent investigations have revealed that the intracellular cargo delivery efficiency of exosomes is compromised under wound hypoxic conditions due to activated hypoxia-induced endocytic recycling 18 , 19 . This limitation significantly impedes their therapeutic efficacy and necessitates approaches to enhance exosome delivery in hypoxic wound tissues.…”

Section: Introductionmentioning

confidence: 99%

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Exosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing

Han,

Saengow,

et al. 2024

Nat Commun

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Wound healing is an obvious clinical concern that can be hindered by inadequate angiogenesis, inflammation, and chronic hypoxia. While exosomes derived from adipose tissue-derived stem cells have shown promise in accelerating healing by carrying therapeutic growth factors and microRNAs, intracellular cargo delivery is compromised in hypoxic tissues due to activated hypoxia-induced endocytic recycling. To address this challenge, we have developed a strategy to coat oxygen nanobubbles with exosomes and incorporate them into a polyvinyl alcohol/gelatin hybrid hydrogel. This approach not only alleviates wound hypoxia but also offers an efficient means of delivering exosome-coated nanoparticles in hypoxic conditions. The self-healing properties of the hydrogel, along with its component, gelatin, aids in hemostasis, while its crosslinking bonds facilitate hydrogen peroxide decomposition, to ameliorate wound inflammation. Here, we show the potential of this multifunctional hydrogel for enhanced healing, promoting angiogenesis, facilitating exosome delivery, mitigating hypoxia, and inhibiting inflammation in a male rat full-thickness wound model.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing

Han,

Saengow,

et al. 2024

Nat Commun

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“…The modified EVs restored the cellular uptake rate, delivered Prx2 into NP cells and inhibited TNF-αinduced pyroptosis. In another study, Tong et al [34] investigated whether the delivery efficiency of MSC-EVs was decreased in NP cells under hypoxic conditions because of an increase in endocytic recycling. Hypoxia inducible factor-1 (HIF-1)-induced upregulation of Rabcoupling protein (RCP), which is also known as RAB11 family interacting protein 1 (RAB11FIP1), promoted the Rab11a-dependent recycling of internalized MSC-EVs by facilitating the interaction between Rab11a and MSC-EVs.…”

Section: Discussionmentioning

confidence: 99%

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission

Lin,

Xu,

et al. 2024

J Nanobiotechnol

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Background Cartilaginous endplate (CEP) degeneration, which is an important contributor to intervertebral disc degeneration (IVDD), is characterized by chondrocyte death. Accumulating evidence has revealed that dynamin-related protein 1 (Drp1)-mediated mitochondrial fission and dysfunction lead to apoptosis during CEP degeneration and IVDD. Exosomes are promising agents for the treatment of many diseases, including osteoporosis, osteosarcoma, osteoarthritis and IVDD. Despite their major success in drug delivery, the full potential of exosomes remains untapped. Materials and methods In vitro and in vivo models of CEP degeneration were established by using lipopolysaccharide (LPS). We designed genetically engineered exosomes (CAP-Nrf2-Exos) expressing chondrocyte-affinity peptide (CAP) on the surface and carrying the antioxidant transcription factor nuclear factor E2-related factor 2 (Nrf2). The affinity between CAP-Nrf2-Exos and CEP was evaluated by in vitro internalization assays and in vivo imaging assays. qRT‒PCR, Western blotting and immunofluorescence assays were performed to examine the expression level of Nrf2 and the subcellular localization of Nrf2 and Drp1. Mitochondrial function was measured by the JC-1 probe and MitoSOX Red. Mitochondrial morphology was visualized by MitoTracker staining and transmission electron microscopy (TEM). After subendplate injection of the engineered exosomes, the degree of CEP degeneration and IVDD was validated radiologically and histologically. Results We found that the cargo delivery efficiency of exosomes after cargo packaging was increased by surface modification. CAP-Nrf2-Exos facilitated chondrocyte-targeted delivery of Nrf2 and activated the endogenous antioxidant defence system in CEP cells. The engineered exosomes inhibited Drp1 S616 phosphorylation and mitochondrial translocation, thereby preventing mitochondrial fragmentation and dysfunction. LPS-induced CEP cell apoptosis was alleviated by CAP-Nrf2-Exo treatment. In a rat model of CEP degeneration, the engineered exosomes successfully attenuated CEP degeneration and IVDD and exhibited better repair capacity than natural exosomes. Conclusion Collectively, our findings showed that exosome-mediated chondrocyte-targeted delivery of Nrf2 was an effective strategy for treating CEP degeneration. Graphic abstract CAP-Nrf2-Exos delivered Nrf2 into CEP cells and alleviated LPS-induced apoptosis by inhibiting Drp1-mediated mitochondrial fission

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“…Significant progress has been made in the treatment of IDD by MSCs, but due to the harsh environment of the IDs[ 5 ], the therapeutic effect of MSCs is reduced due to the lack of oxygen in the environment[ 61 ]. However, it has been found that the differentiation of MSCs to chondrocytes under hypoxic conditions can be helped by the addition of leptin[ 62 ], which provides energy for cell differentiation through its dependent glycolysis.…”

Section: Harsh Environment Of the Idmentioning

confidence: 99%

How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

Zhang,

Cui

2023

World J Stem Cells

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Intervertebral disc (ID) degeneration (IDD) is one of the main causes of chronic low back pain, and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID. The environment in which the ID is located is harsh, with almost no vascular distribution within the disc, and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate. The stability of its internal environment also plays an important role in preventing IDD. The main feature of disc degeneration is a decrease in the number of cells. Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner. The main purpose is to promote their regeneration. The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix. The treatment of disc degeneration with stem cells has achieved good efficacy, and the current challenge is how to improve this efficacy. Here, we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles, enhancement of therapeutic effects when stem cells are mixed with related substances, and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions. We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.

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Augmenting Intracellular Cargo Delivery of Extracellular Vesicles in Hypoxic Tissues through Inhibiting Hypoxia-Induced Endocytic Recycling

Cited by 14 publications

References 53 publications

Exosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing

Exosome-coated oxygen nanobubble-laden hydrogel augments intracellular delivery of exosomes for enhanced wound healing

Chondrocyte-targeted exosome-mediated delivery of Nrf2 alleviates cartilaginous endplate degeneration by modulating mitochondrial fission

How to enhance the ability of mesenchymal stem cells to alleviate intervertebral disc degeneration

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