Journal of translational medicine · 2026
Targeted delivery of USP10 via neutrophil membrane-coated biomimetic nanoparticle facilitates cardiac repair through AMPK-dependent anti-apoptotic and pro-angiogenic pathways.
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Zhuang Jiawei, Xu Jiacheng, Wang Jiamao, Huang Jian, Zhou Xiaobiao, Zhu Zhuanghui, Cheng Gangyi, Bai Haoyu, Li Li, Shan Zhonggui
Аннотация
BACKGROUND: Extensive loss of cardiomyocytes plays a major role in heart failure development after myocardial infarction (MI). Existing pharmacological treatments targeting cardiomyocyte apoptosis have shown limited clinical efficacy, largely because the underlying molecular mechanisms are unclear and effective drug delivery systems are unavailable. Emerging evidence suggests a critical regulatory role of ubiquitin-specific peptidase 10 (USP10) in cardiomyocyte apoptosis through multiple pathways.
METHODS: USP10 expression and its association with cardiomyocyte apoptosis were evaluated in a murine MI model. A biomimetic nanoparticle coated with neutrophil membranes and encapsulating a USP10 overexpression plasmid (NM-NP-USP10) was developed and characterized. Subsequent investigations evaluated its biodistribution, biosafety, therapeutic efficacy, and underlying mechanisms both in vivo and in vitro. The role of AMPK signaling was examined through the application of the pharmacological inhibitor Compound C.
RESULTS: USP10 expression was markedly downregulated in the infarcted cardiac tissue and showed a positive association with cardiomyocyte apoptosis. NM-NP-USP10 preferentially accumulated in the ischemic myocardium and exhibited favorable biosafety profiles. Moreover, treatment with NM-NP-USP10 not only attenuated cardiomyocyte apoptosis but also promoted angiogenesis in vivo. Mechanistically, NM-NP-USP10 activated the AMPK/Akt/eNOS signaling pathway. In contrast, inhibition of AMPK substantially abrogated its anti-apoptotic and pro-angiogenic effects, indicating that AMPK signaling serves as a critical mediator of USP10-induced cardioprotection.
CONCLUSIONS: These findings identify USP10 as a protective regulator in MI and demonstrate that targeted delivery of USP10 via neutrophil membrane-coated biomimetic nanoparticles facilitates cardiac repair through AMPK-dependent anti-apoptotic and pro-angiogenic mechanisms, underscoring its potential as a therapeutic strategy for MI.
METHODS: USP10 expression and its association with cardiomyocyte apoptosis were evaluated in a murine MI model. A biomimetic nanoparticle coated with neutrophil membranes and encapsulating a USP10 overexpression plasmid (NM-NP-USP10) was developed and characterized. Subsequent investigations evaluated its biodistribution, biosafety, therapeutic efficacy, and underlying mechanisms both in vivo and in vitro. The role of AMPK signaling was examined through the application of the pharmacological inhibitor Compound C.
RESULTS: USP10 expression was markedly downregulated in the infarcted cardiac tissue and showed a positive association with cardiomyocyte apoptosis. NM-NP-USP10 preferentially accumulated in the ischemic myocardium and exhibited favorable biosafety profiles. Moreover, treatment with NM-NP-USP10 not only attenuated cardiomyocyte apoptosis but also promoted angiogenesis in vivo. Mechanistically, NM-NP-USP10 activated the AMPK/Akt/eNOS signaling pathway. In contrast, inhibition of AMPK substantially abrogated its anti-apoptotic and pro-angiogenic effects, indicating that AMPK signaling serves as a critical mediator of USP10-induced cardioprotection.
CONCLUSIONS: These findings identify USP10 as a protective regulator in MI and demonstrate that targeted delivery of USP10 via neutrophil membrane-coated biomimetic nanoparticles facilitates cardiac repair through AMPK-dependent anti-apoptotic and pro-angiogenic mechanisms, underscoring its potential as a therapeutic strategy for MI.