SIRT1 targeted bioengineered extracellular vesicles chrono-reprogram microglia to reverse non-dipping hypertension - myocardial remodeling and comorbid neuropsychiatric disorders under stress

Sep 16, 2025International immunopharmacology

Bioengineered particles targeting SIRT1 reset brain immune cells’ daily rhythm to reverse nighttime high blood pressure, heart changes, and stress-related mental disorders

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Abstract

Genetic CLOCK ablation led to anxiety/depressive behaviors and was associated with restored Sirt1-HMGB1 homeostasis and normalized blood pressure rhythms.

Chronic stress-induced neuroinflammation may drive stress-induced hypertension through dysregulation of CLOCK in microglia.
Sustained hypertension was observed alongside disrupted blood pressure circadian rhythms and altered cytokine levels in the rostral ventrolateral medulla.
Stress caused CLOCK upregulation that interfered with Sirt1 activity, leading to changes in HMGB1 modifications.
Microglia-specific Sirt1 overexpression using bioengineered extracellular vesicles improved mitochondrial function and reversed myocardial remodeling.
MG-Sirt1-EVs demonstrated greater effectiveness than SRT1720 in restoring blood pressure rhythms and alleviating hypertension.

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Chronic stress-induced neuroinflammation within autonomic brain nuclei drives stress-induced hypertension (SIH), yet circadian-neuroimmune mechanisms underlying maladaptive hemodynamic rhythms remain unclear. We delineate a novel chronobiological axis where CLOCK dysregulation in rostral ventrolateral medulla (RVLM) microglia orchestrates non-dipping hypertension via Sirt1-dependent polarization and redox-sensitive HMGB1 modifications. Using a foot-shock noise stress paradigm, we observed sustained hypertension with disrupted BP circadian rhythms, attenuated CLOCK oscillations, and diurnal cytokine dysrhythmia in RVLM microglia. Mechanistically, stress-induced CLOCK upregulation disrupted Sirt1 activity via mitochondrial ROS, driving HMGB1 acetylation and ds-HMGB1 release. RVLM CLOCK knockout (Cre-CX3CR1/CLOCK) restored Sirt1-HMGB1 homeostasis, normalized cytokine rhythms, and rescued BP chronobiology. SRT1720 attenuated HMGB1 hyperacetylation and reversed non-dipping hypertension. Notably, genetic CLOCK ablation caused anxiety/depressive behaviors, while whole-brain Sirt1 overexpression induced astrocyte A1 polarization with emotional deficits, highlighting microglia-specific Sirt1 modulation necessity. To target the mitochondria-Sirt1 axis precisely, we engineered bioengineered extracellular vesicles (MG-Sirt1-EVs) for microglia-specific Sirt1 overexpression. Beyond rescuing RVLM mitochondrial homeostasis, circadian oscillations, and neuroinflammation - MG-Sirt1-EVs reversed stress-induced myocardial remodeling: Masson's trichrome/WGA staining revealed reduced fibrosis and normalized cardiomyocyte size; echocardiography showed improved diastolic function (elevated E/A ratio); TH immunostaining and HRV LF/HF ratio confirmed attenuated sympathetic overactivity; molecular markers (BNP, cTnT) were downregulated. MG-Sirt1-EVs outperformed SRT1720 in rest-phase hemodynamic efficacy, reversing non-dipping hypertension while restoring BP rhythms. Dual benefits in cardiovascular (myocardial remodeling reversal) and neuropsychiatric (behavioral rescue) domains were consistently observed. Our findings establish CLOCK/Sirt1-mediated microglial activation as a driver of neuroimmune-cardiovascular dysregulation, offering a translational macromolecule platform for chrono-immunotherapy of comorbid disorders. fl/fl

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SIRT1 targeted bioengineered extracellular vesicles chrono-reprogram microglia to reverse non-dipping hypertension - myocardial remodeling and comorbid neuropsychiatric disorders under stress

Abstract

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