Engineered exosomes enriched in netrin-1 modRNA promote axonal growth in spinal cord injury by attenuating inflammation and pyroptosis

Lu, Xiao; Xu, Guangyu; Lin, Zhidi; Zou, Fei; Liu, Siyang; Zhang, Yuxuan; Fu, Wei; Jiang, Jianyuan; Ma, Xiaosheng; Song, Jian

doi:10.1186/s40824-023-00339-0

Cited by 25 publications

(15 citation statements)

References 76 publications

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“…ModRNAs, which are novel gene vectors, are transferred into target cells to achieve facile and controllable expression of target proteins. ,, Moreover, encapsulation of medications within exosomes can prevent monocyte phagocytosis and enzymatic degradation in the cellular matrix in vivo . To enhance the therapeutic efficacy, MSCs are often genetically modified by exogenous genetic transfection based on disease-specific characteristics. ,, To enhance the therapeutic potential of exosomes and improve the prognosis of OA, we used modRNA technology to genetically modify exosomes with Atf5. This study confirmed that Ex modAtf5 released from Gel@Ex modAtf5 were highly effective in preventing OA progression in vivo and in vitro .…”

Section: Discussionmentioning

confidence: 99%

“…18 Recently, our team documented the benefits of exosomes containing netrin-1 modRNA for the treatment of spinal cord injury. 19 Exosomes derived from cells involve in intercellular material transport and information transmission that exhibit excellent stability, biocompatibility, permeability, and low immunogenicity. 20 Genetically engineered cells can endow exosomes with novel functionalities by delivering bioactive substances, thereby enabling their use as targeted drug delivery vehicles for small molecules, nucleic acids, or drugs to specific cell types or tissues.…”

Section: ■ Introductionmentioning

confidence: 99%

“…Modified mRNA (modRNA) has emerged as a highly efficient gene delivery vector for nucleic acid therapy. , The technology employs various modified bases, such as N1-methylpseudouridine, to synthesize DNA templates that carry mRNA biological information in vitro and subsequently transcribe modRNA molecules. , In comparison to DNA/viral-based technologies, modRNA enables potent and transient gene delivery, allowing for the expression of highly efficient and controllable amounts of protein with minimal immunogenicity . Recently, our team documented the benefits of exosomes containing netrin-1 modRNA for the treatment of spinal cord injury . Exosomes derived from cells involve in intercellular material transport and information transmission that exhibit excellent stability, biocompatibility, permeability, and low immunogenicity .…”

Section: Introductionmentioning

confidence: 99%

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Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response

Ma,

Xu,

Gao

et al. 2024

ACS Appl. Mater. Interfaces

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Osteoarthritis (OA) progression is highly associated with chondrocyte mitochondrial dysfunction and disorders of catabolism and anabolism of the extracellular matrix (ECM) in the articular cartilage. The mitochondrial unfolded protein response (UPRmt), which is an integral component of the mitochondrial quality control (MQC) system, is essential for maintaining chondrocyte homeostasis. We successfully validated the pivotal role of activating transcription factor 5 (ATF5) in upregulating the UPRmt, mitigating IL-1β-induced inflammation and mitochondrial dysfunction, and promoting balanced metabolism in articular cartilage ECM, proving its potential as a promising therapeutic target for OA. Modified mRNAs (modRNAs) have emerged as novel and efficient gene delivery vectors for nucleic acid therapeutic approaches. In this study, we combined Atf5-modRNA (modAtf5) with engineered exosomes derived from bone mesenchymal stem cells (ExmodAtf5) to exert cytoprotective effects on chondrocytes in articular cartilage via Atf5. However, the rapid localized metabolization of ExmodAtf5 limits its application. PLGA–PEG-PLGA (Gel), an injectable thermosensitive hydrogel, was used as a carrier of ExmodAtf5 (Gel@ExmodAtf5) to achieve a sustained release of ExmodAtf5. In vitro and in vivo, the use of Gel@ExmodAtf5 was shown to be a highly effective strategy for OA treatment. The in vivo therapeutic effect of Gel@ExmodAtf5 was evidenced by the preservation of the intact cartilage surface, low OARSI scores, fewer osteophytes, and mild subchondral bone sclerosis and cystic degeneration. Consequently, the combination of ExmodAtf5 and PLGA–PEG-PLGA could significantly enhance the therapeutic efficacy and prolong the exosome release. In addition, the mitochondrial protease ClpP enhanced chondrocyte autophagy by modulating the mTOR/Ulk1 pathway. As a result of our research, Gel@ExmodAtf5 can be considered to be effective at alleviating the progression of OA.

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Section: Discussionmentioning

confidence: 99%

Section: ■ Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response

Ma,

Xu,

Gao

et al. 2024

ACS Appl. Mater. Interfaces

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“…These conditions impose an important financial burden on the affected individuals, the respective families and society. Excitotoxicity, neuroinflammation, lipid peroxidation, ischemia–reperfusion injury, and free radical production are key pathological processes and microenvironment imbalances following SCI that impede its repair 1,2 . SCI generally results in sensorimotor and autonomic nerve injuries and is still considered an important public health concern globally.…”

Section: Introductionmentioning

confidence: 99%

Necroptosis pathway emerged as potential diagnosis markers in spinal cord injury

Liu,

Cao,

et al. 2024

J Cellular Molecular Medi

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The present research focused on identifying necroptosis‐related differentially expressed genes (NRDEGs) in spinal cord injury (SCI) to highlight potential therapeutic and prognostic target genes in clinical SCI. Three SCI‐related datasets were downloaded, including GSE151371, GSE5296 and GSE47681. MSigDB and KEGG datasets were searched for necroptosis‐related genes (NRGs). Differentially expressed genes (DEGs) and NRGs were intersected to obtain NRDEGs. The MCC algorithm was employed to select the first 10 genes as hub genes. A protein–protein interaction (PPI) network related to NRDEGs was developed utilizing STRING. Several databases were searched to predict interactions between hub genes and miRNAs, transcription factors, potential drugs, and small molecules. Immunoassays were performed to identify DEGs using CIBERSORTx. Additionally, qRT‐PCR was carried out to verify NRDEGs in an animal model of SCI. Combined analysis of all datasets identified 15 co‐expressed DEGs and NRGs. GO and KEGG pathway analyses highlighted DEGs mostly belonged to pathways associated with necroptosis and apoptosis. Hub gene expression analysis showed high accuracy in SCI diagnosis was associated with the expression of CHMP7 and FADD. A total of two hub genes, i.e. CHMP7, FADD, were considered potential targets for SCI therapy.

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“…The complex and diverse pathophysiological processes and microenvironmental imbalances following SCI, including excitotoxicity, lipid peroxidation, neuroinflammation, ischemia-reperfusion injury, and the production of free radicals, 1,2 are the important reasons for the difficult repair of SCI. There are still no effective repair options available.…”

Section: Introductionmentioning

confidence: 99%

Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53‐ALOX15 signaling pathway

et al. 2023

CNS Neurosci Ther

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Background Spinal cord injury (SCI) is a highly disabling condition in spinal surgery that leads to neuronal damage and secondary inflammation. Ferroptosis is a non‐apoptotic type of cell death that has only recently been identified, which is marked primarily by iron‐dependent and lipid‐derived reactive oxygen species accumulation, and accompanied by morphological modifications such as mitochondrial atrophy and increase in membrane density. Dihydroorotate dehydrogenase (DHODH) is a powerful inhibitor of ferroptosis and has been demonstrated to inhibit cellular ferroptosis in tumor cells, but whether it can inhibit neuronal injury following spinal cord injury remains ambiguous. Methods In this study, the effect of DHODH on neuronal ferroptosis was observed in vivo and in vitro using a rat spinal cord injury model and erastin‐induced PC12 cells, respectively. A combination of molecular and histological approaches was performed to assess ferroptosis and explore the possible mechanisms in vivo and in vitro. Results First, we confirmed the existence of neuronal ferroptosis after spinal cord injury and that DHODH attenuates neuronal damage after spinal cord injury. Second, we showed molecular evidence that DHODH inhibits the activation of ferroptosis‐related molecules and reduces lipid peroxide production and mitochondrial damage, thereby reducing neuronal ferroptosis. Further analysis suggests that P53/ALOX15 may be one of the mechanisms regulated by DHODH. Importantly, we determined that DHODH inhibits ALOX15 expression by inhibiting P53. Conclusions Our findings reveal a novel function for DHODH in neuronal ferroptosis after spinal cord injury, suggesting a unique therapeutic target to alleviate the disease process of spinal cord injury.

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Engineered exosomes enriched in netrin-1 modRNA promote axonal growth in spinal cord injury by attenuating inflammation and pyroptosis

Cited by 25 publications

References 76 publications

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response

Engineered Exosomes with ATF5-Modified mRNA Loaded in Injectable Thermogels Alleviate Osteoarthritis by Targeting the Mitochondrial Unfolded Protein Response

Necroptosis pathway emerged as potential diagnosis markers in spinal cord injury

Dihydroorotate dehydrogenase regulates ferroptosis in neurons after spinal cord injury via the P53‐ALOX15 signaling pathway

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