Spinal cord injury (SCI) is a devastating disease that causes major motor, sensory and autonomic dysfunctions. Currently, there is a lack of effective treatment. In this study, we aimed to investigate the potential mechanisms of Exosomes from adipose-derived stem cells (ADSC-Exos) in reducing ferroptosis and promoting angiogenesis after spinal cord injury. We isolated ADSC-Exos, the characteristics of which were confirmed. In vitro, we tested the potential of ADSC-Exos to promote the survival and function of human brain microvascular endothelial cells (HBMECs) and analyzed the ferroptosis of HBMECs. In vivo, we established rat models of SCI and locally injected ADSC-Exos to verify their efficacy. ADSC-Exos can reduce reactive oxygen species (ROS) accumulation and cell damage induced by an excessive inflammatory response in HBMECs. ADSC-Exos inhibit ferroptosis induced by excessive inflammation and upregulate the expression of glutathione peroxidase 4(GPX4) in HBMECs. It can also effectively promote proliferation, migration, and vessel-like structure formation. In vitro, ADSC-Exos improved behavioral function after SCI and increased the number and density of blood vessels around the damaged spinal cord. Moreover, we found that ADSC-Exos could increase nuclear factor erythroid-2-related factor 2(NRF2) expression and nuclear translocation, thereby affecting the expression of solute carrier family 7 member 11(SLC7A11) and GPX4, and the NRF2 inhibitor ML385 could reverse the above changes. Our results suggest that ADSC-Exos may inhibit ferroptosis and promote the recovery of vascular and neural functions after SCI through the NRF2/SLC7A11/GPX4 pathway. This may be a potential therapeutic mechanism for spinal cord injury.

The immune‐inflammatory responses in the brain represent a key therapeutic target to ameliorate brain injury following intracerebral hemorrhage (ICH), where pro‐inflammatory microglia and its mitochondrial dysfunction plays a pivotal role. Mitochondrial transplantation is a promising strategy to improve the cellular mitochondrial function and thus modulate their immune properties. However, the transplantation of naked mitochondria into the brain has been constrained by the peripheral clearance and the difficulty in achieving selective access to the brain. Here, a novel strategy for mitochondrial transplantation via intravenous injection of magnetically responsive artificial cells (ACs) are proposed. ACs can protect the loaded mitochondria and selectively accumulate around the lesion under an external magnetic field (EMF). In this study, mitochondria released from ACs can effectively improve microglial mitochondrial function, attenuate their pro‐inflammatory attributes, and elevate the proportion of immunosuppressive microglia. In this way, microglia immune homeostasis in the brain is reestablished, and inflammation is attenuated, ultimately promoting functional recovery. This study presents an effective approach to transplant mitochondria into the brain, offering a promising alternative to modulate the immune‐inflammatory cascade in the brain following ICH.

Vulnerable plaque rupture is the main trigger of most acute cardiovascular events. But the underlying mechanisms responsible for the transition from stable to vulnerable plaque remain largely unknown. Nuclear receptor subfamily 1 group D member 1 (NR1D1), also known as REV‐ERB α, is a nuclear receptor that has shown the protective role in cardiovascular system. However, the effect of NR1D1 on vulnerable plaque rupture and its underlying mechanisms are still unclear. By generating the rupture‐prone vulnerable plaque model in hypercholesterolemic ApoE^−/− mice and NR1D1^−/−ApoE^−/− mice, we demonstrated that NR1D1 deficiency significantly augmented plaque vulnerability/rupture, with higher incidence of intraplaque hemorrhage (78.26% vs. 47.82%, P = 0.0325) and spontaneous plaque rupture with intraluminal thrombus formation (65.21% vs. 39.13%, P = 0.1392). In vivo experiments indicated that NR1D1 exerted a protective role in the vasculature. Mechanically, NR1D1 deficiency aggravates macrophage infiltration, inflammation, and oxidative stress. Compared with the ApoE^−/− mice, NR1D1^−/−ApoE^−/− mice exhibited a significantly higher expression level of pyroptosis‐related genes in macrophages within the plaque. Further investigation based on mice bone marrow‐derived macrophages (BMDMs) confirmed that NR1D1 exerted a protective effect by inhibiting macrophage pyroptosis in a NLRP3‐inflammasome‐dependent manner. Besides, pharmacological activation of NR1D1 by SR9009, a specific NR1D1 agonist, prevented plaque vulnerability/rupture. In general, our findings provide further evidences that NR1D1 plays a protective role in the vasculature, regulates inflammation and oxidative stress, and stabilizes rupture‐prone vulnerable plaques.

The pro‐inflammatory immune microenvironment in the localized lesion areas and the absence of DNA damage repair mechanisms in endothelial cells serve as essential accelerating factors in the development of atherosclerosis. The lack of targeted therapeutic strategies represents a significant limitation in the efficacy of therapeutic agents for atherosclerosis. In this study, Genetically engineered SNHG12‐loaded cerium‐macrophage exosomes (Ce‐Exo) are designed as atherosclerosis‐targeting agents. In vivo studies demonstrated that Ce‐Exo exhibited multivalent targeting properties for macrophages, with a 4.1‐fold higher atherosclerotic plaque‐aggregation ability than that of the control drugs. This suggests that Ce‐Exo has a higher homing capacity and deeper penetration into the atherosclerotic plaque. In apolipoprotein E‐deficient mice, Ce‐Exo found to effectively remodel the immune microenvironment in the lesion area, repair endothelial cell damage, and inhibit the development of atherosclerosis. This study provides a novel approach to the treatment of atherosclerosis and demonstrates the potential of cell‐derived drug carriers in biomedicine.

An increasing amount of evidence shows that type I interferon response, which is induced by cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) and stimulator of interferon genes (STING) is closely associated with health and neuroinflammatory diseases. Abnormal activation or loss of control of the cGAS–STING axis affects the development of neuroinflammation. Thus, we examined its role in major neurological diseases, including traumatic brain injury, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, herpes simplex encephalitis, and ataxia-telangiectasia. Additionally, targeted intervention of the cGAS–STING axis to control neuroinflammation and treat related diseases has become the focus of current clinical research. This article describes the development of cGAS inhibitors and small molecules that target the cGAS–STING axis and explores the potential applications of STING inhibitors and agonists in clinical research. In summary, the cGAS–STING axis may impact neurological diseases more than a single protein or gene. Future studies should focus on elucidating the functional dynamics and regulatory networks of this axis and delineating its crosstalk with other signaling cascades. These investigations will provide mechanistic insights for developing targeted therapeutic strategies for associated disorders and potentially facilitate drug repurposing across diverse disease contexts.