Previous studies have found that activated CD8 + T cells secrete elevated levels of interferon-gamma (IFN-𝜸) to trigger ferroptosis in tumor cells. However, IFN-𝜸-mediated ferroptosis is induced at low levels in tumor cells because of the limited IFN-𝜸 secreted by CD8 + T cells in the immunosuppressive tumor microenvironment. Recent studies have shown that manganese ion can activate the cyclic guanosine monophosphate-adenosine monophosphate (GMP-AMP) synthase/stimulator of interferon genes (cGAS-STING) pathway and support adaptive immune responses against tumors, which enhances the level of tumor-infiltrating CD8 + T cells. Therefore, tumor microenvironment-responsive Mn-based nanoenzymes (Mn-based NEs) that activated the cGAS-STING pathway are designed to amplify immune-driven ferroptosis.The multifunctional all-in-one nanoplatform is simply and mildly synthesized by the coordination between Mn 3+ ions and 3,3′-dithiodipropionic acid. After intracellular delivery, each component of Mn-based NEs exerts its function. That is, glutathione is depleted through disulfide-thiol exchange and redox pair of Mn 3+ /Mn 2+ , a hydroxyl radical (•OH) is generated via the Fenton-like reaction to cause ferroptosis, and Mn 2+ augments cGAS-STING activity to boost immune-driven ferroptosis. In addition, ferroptosis amplifies Mn 2+ -induced immunogenic cell death and initiates the antitumor immune "closed loop" along with immune-driven ferroptosis. Notably, this multifunctional nanoplatform is effective in killing both primary and distant tumors.

BackgroundEarly diagnosis of hospitalized elderly patients with infectious stress hyperglycaemia (ISH) is clinically important, especially under the global coronavirus disease 2019 (COVID‐19) pandemic, as without timely prevention and effective treatment, it is likely to deteriorate into septic shock, thus worsening patient survival and complications. Moreover, cumulative studies have showed that patients with COVID‐19 are reported to have a greater prevalence of hyperglycaemia. However, the underlying mechanism remained unknown.Aim and methodSystematic screening of specific biomarkers of serum exosome‐derived microRNAs (sE‐miRNAs) from ISH patient has not yet been reported. In this study, sE‐miRNAs were derived from 10 elderly patients with ISH and 5 control patients with disease‐match without hyperglycaemia (non‐ISH). RNA sequencing identified that a total number of 49 sE‐miRNAs with differential expression between ISH and control group. Of which, top 22 miRNAs ranked by sensitivity × specificity were chosen for further research. Moreover, 7 out of 22 miRNAs that related to glucose metabolism or immune disorder were picked up for further validation in an independent cohort consisting of 52 participants (31 ISH and 21 non‐ISH).ResultA validation analysis revealed that three miRNAs (hsa‐miR‐21‐5p, hsa‐miR‐335‐5p and hsa‐miR‐28‐3p) were statistically up‐regulated in exosomes from ISH patients. In the validation cohort and discovery cohort, the AUC of three individual miRNAs ranged from 0.73 to 0.88. A logistic model combining three miRNAs achieved an AUC of 0.96. Besides, sE‐miRNAs‐based signatures effectively characterized patients' poor clinical outcome. Survival curve analysis showed that hsa‐miR‐335‐5p, hsa‐miR‐28‐3p but not hsa‐miR‐21‐5p, were significantly closely related to mortality, and the combination of these three miRNAs could also predict patients outcome (p < .05).ConclusionThis study depicted the circulating exosomal miRNAs change in ISH patient, which could be used as a promising biomarker to detect ISH at an early stage and predict patients clinical outcome.

Early diagnosis of hospitalized elderly patients with infectious stress hyperglycaemia (ISH) is clinically important, as without timely prevention and effective treatment, it is likely to deteriorate into septic shock, which significantly worsen patients’ survival rate. Systematic screening of specific biomarkers of serum small extracellular vesicles (sEVs) from ISH patient has not yet been reported. In this study, serum sEVs were derived from 10 elderly patients with ISH and 5 control patients with disease-match without hyperlycemia (non-ISH). RNA sequencing identified a total number of 49 sEVs enriched fraction derived miRNAs with differential expression between ISH and control group. Of which, top 22 miRNAs ranked by sensitivity × specificity were chosen for further research. Moreover,7 out of 22 miRNAs that related to glucose metabolism or immune disorder, were picked up for further validation in an independent cohort consisting of 52 participants (31 ISH and 21 non-ISH). A validation analysis revealed that 3 miRNAs (hsa-miR-21-5p，hsa-miR-335-5p，hsa-miR-28-3p) were statistically up-regulated in exosomes from ISH patients. In the validation cohort and discovery cohort, the AUC of 3 individual miRNAs ranged from 0.73 to 0.88. A logistic model combining three miRNAs achieved an AUC of 0.96. Besides,sEV‐miRNA‐based signatures effectively characterized patients’ poor clinical outcome. Survival curve analysis showed that miR-335-5p, miR-28-3p but not miR-21-5p, were significantly closely related to mortality, and the combination of the three could also predict patients outcome.(P<0.05).This study depicted the circulating exosomal miRNAs change in ISH patient and which could be used as a promising biomarker to detect ISH at an early stage, and predict patients clinical outcome.