As a common chronic metabolic disease, diabetes mellitus (DM) features a hyperglycemic micromilieu around implants, resulting in the critical implantation failure and high complications such as peri-implantitis and angiectasis disorder. To address the plaguing issue, we devise and develop a glucose-unlocked NO-evolving orthopedic implant consisted of polyetheretherketone (PEEK), glucose oxidase (GOx) and l-arginine (Arg) with enhanced angiogenesis for boosting diabetic osseointegration. Upon hyperglycemic niche, GOx on implants catalytically exhaust glucose to H2O2, which immediately reacts with Arg to in situ liberate nitric oxide (NO), resulting in enhanced angiogenesis and angiectasis around PEEK implant. Besides, the engineered implant exhibits great anti-bacterial properties against both Gram-positive and Gram-negative bacteria, as well as fortifies osteogenicity of osteoblasts in terms of cell proliferation, alkaline phosphatase activity and calcium matrix mineralization. Intriguingly, in vivo evaluations utilizing diabetic infectious bone defect models of rat further authenticate that the engineered implants substantially augment bone remodeling and osseointegration at weeks 4 and 8 through dampening pathogens, anti-inflammatory as well as promoting angiectasis. Altogether, this work proposed a new tactic to remedy stalled diabetic osseointegration with hyperglycemic micromilieu-responsive therapeutic gas-evolving orthopedic implants.

Cardiovascular diseases (CVDs) are vital causes of global mortality. Apart from lifestyle intervention like exercise for high-risk groups or patients at early period, various medical interventions such as percutaneous coronary intervention (PCI) and coronary artery bypass graft (CABG) surgery have been clinically used to reduce progression and prevalence of CVDs. However, invasive surgery risk and severe complications still contribute to ventricular remodeling, even heart failure. Innovations in nanomedicines have fueled impressive medical advances, representing a CVD therapeutic alternative. Currently, clinical translation of nanomedicines from bench to bedside continues to suffer unpredictable biosafety and orchestrated behavior mechanism, which, if appropriately addressed, might pave the way for their clinical implementation in the future. While state-of-the-art advances in CVDs nanomedicines are widely summarized in this review, the focus lies on urgent preclinical concerns and is transitioned to the ongoing clinical trials including stem cells-based, extracellular vesicles (EV)-based, gene, and Chimeric Antigen Receptor T (CAR T) cell therapy whose clinically applicable potential in CVD therapy will hopefully provide first answers. Overall, this review aims to provide a concise but comprehensive understanding of perspectives and challenges of CVDs nanomedicines, especially from a clinical perspective.

Porphyromonas gingivalis (P.g.), a pathogen linked to periodontitis, is reported to be associated with severe neurocognitive dysfunction. However, there are few reports focusing on improving neurological function in the brain by eliminating P.g.. Therefore, we developed a core-shell nanocomposite for targeted intracerebral P.g. clearance and ameliorating neurocognitive impairments, Pt-Au@C-P.g.-MM, consisting of platinum nanoparticles (Pt NPs) encapsulated within Au nanocages (Pt-Au) as the core and a shell made of collagen and macrophage membranes from macrophage pretreated with P.g. (C-P.g.-MM). This design enhanced the nanocomposite's ability to cross the blood-brain barrier (BBB) and specifically target intracerebral P.g. through coating of P.g.-MM. Pt-Au@C-P.g.-MM depended on collagen to neutralize excessive collagenase from P.g., promoting its directed migration toward P.g.. Au nanocages exhibited excellent photothermal effects under near-infrared (NIR) laser irradiation, while Pt NPs also provided an efficient antibacterial gas therapy by generating oxygen to expose anaerobic P.g.. As a result, Pt-Au@C-P.g.-MM contributed to a synergistic antibacterial therapy and significantly reduced P.g. mediated neurocognitive dysfunction in periodontitis mice induced by oral P.g. infection. Based on the insights provided by the transcriptome sequencing analysis, anti-P.g. activity of Pt-Au@C-P.g.-MM facilitated the transition of microglia from the M1 to M2 phenotype by stimulating the PI3K-Akt pathway and reducing neuronal damage through the Wnt/β-catenin pathway.

Global industrialization has resulted in severe contamination of soil with heavy metals (HMs). Nevertheless, it is unclear if it affects the depth-resolved bacterial communities. Herein, we collected soil samples at different depths from a typical HM-contaminated site and used amplicon sequencing to determine the differences in depth-resolved bacterial communities and to assess the thresholds and ecological impacts of HMs. Results revealed that HM levels reduced markedly with soil depth. The bacteria in upper soil exhibited higher community diversity and a more complex and stable ecological network structure. As depth increased, the proportion of negative interactions gradually elevated, indicating more competitive interspecies behavior. Threshold analyses based on machine learning revealed that arsenic (As) and copper (Cu) exhibited nonlinear impacts on ecosystems. Cu demonstrated a low-threshold effect, with its ecological consequences manifested at extremely low concentrations. Our results highlighted the utility of microbial monitoring in assessing the adverse effects of HMs on soil health to support environmental management and ecological restoration.

The balance of antibacterial and osseointegration-promoting properties on titanium (Ti) implants in a simple and efficient manner is crucial for the management of implant-associated infections, a condition that has become a significant global health concern. Herein, a nitric oxide (NO)-mediated dual-function smart coating with antibacterial and osseointegration-promoting properties is developed for Ti implants. The coating leverages the distinct properties of NO at high and low concentrations to enable an on-demand functional switch. Specifically, antibacterial function is achieved through a rapid release of high-dose NO in response to the infection microenvironment and near-infrared stimulation. Once the infection is resolved and normal physiological conditions are restored, the coating gradually releases low-dose NO to promote osseointegration. In vitro tests confirm that the coating exhibits antibacterial ratio of 97.84% and 97.18% against methicillin-resistant Staphylococcus aureus and its biofilms, respectively, and demonstrates the ability to activate osteoblasts. The rat femoral implant-associated infection model further certifies that the responsive NO release mechanism of the coating efficiently facilitates the on-demand functional switch between antibacterial and osseointegration-promoting properties. Notably, the use of the dual-functional nonantibiotic agent, NO, significantly mitigates the risk of bacterial resistance.

Myocardial ischemia-reperfusion injury (MIRI) is fatal to patients, leading to cardiomyocyte death and myocardial remodeling. Reactive oxygen species (ROS) and oxidative stress play important roles in MIRI. There is a complex crosstalk between ROS and regulatory cell deaths (RCD) in cardiomyocytes, such as apoptosis, pyroptosis, autophagy, and ferroptosis. ROS is a double-edged sword. A reasonable level of ROS maintains the normal physiological activity of myocardial cells. However, during myocardial ischemia-reperfusion, excessive ROS generation accelerates myocardial damage through a variety of biological pathways. ROS regulates cardiomyocyte RCD through various molecular mechanisms. Targeting the removal of excess ROS has been considered an effective way to reverse myocardial damage. Many studies have applied antioxidant drugs or new advanced materials to reduce ROS levels to alleviate MIRI. Although the road from laboratory to clinic has been difficult, many scholars still persevere. This article reviews the molecular mechanisms of ROS inhibition to regulate cardiomyocyte RCD, with a view to providing new insights into prevention and treatment strategies for MIRI.

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a non-ionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell (EC) function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and ECs to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs' NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188's therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

Nitric oxide (NO) has shown significant potential in chronic wound healing due to its ability of promoting blood circulation. However, excessive NO can trigger local inflammatory response, potentially hindering wound healing. Therefore, controlled and sustained NO release to minimize pro-inflammation effects during treatment is in great demand for diabetic wounds. Herein, an injectable thiolated chitosan hydrogel loaded with NO donors (GNO) and silver nanoparticles (AgNPs) is presented for effective diabetic wound treatment, from which NO was released stably and sustainably responsive to reactive oxygen species (ROS) at the wound site. The combination of NO and AgNPs demonstrated robust antibacterial activity and biofilm dissipation. During diabetic wound treatments, the sustained release of NO promoted blood vessel regeneration while inhibiting inflammatory factors, thereby accelerating wound healing. This combined approach achieves efficient antibacterial action, biofilm prevention, inflammation suppression, vascular repair, improved local blood circulation, ultimately facilitating the reconstruction of epithelial structures at the wound site, thereby providing a promising solution for the diabetic chronic wound healing.

Myocardial infarction (MI) causes cardiac dysfunction and threatens global health. Timely reperfusion following MI unavoidably contributes to additional cardiomyocyte death, a phenomenon known as myocardial ischemia/reperfusion injury (I/RI). The surge in free radicals and extensive cardiomyocyte loss significantly promote the progression toward heart failure, a condition that remains a major therapeutic challenge. Development of microRNA (miRNA)-based therapeutics for I/RI is hindered by poor intracellular delivery of miRNA and its rapid degradation in vivo. Nanozymes with enzyme-mimetic activities offer promising platforms for miRNA delivery while concurrently mitigating oxidative stress. Hollow ceria nanozymes decorated with gold nanoparticles (AuNPs) are developed to deliver miR-486, whose cavernous rooms enable them to accommodate miRNA. Elevated miR-486 expression is shown to suppress myocardial apoptosis and alleviate I/RI. Equipped with cardiac target peptide, miR-486@CeO2/Au-pep nanoparticles are integrated with superior enzyme-mimicking functions than a single entity, reactive oxygen species (ROS) scavenging, and improved miR-486 delivery. In myocardial I/RI mice, miR-486@CeO2/Au-pep can specifically accumulate at the heart and promote miR-486 to escape from lysosomes, which further boosts the bioactivity of miR-486 in cardiomyocytes. These combined effects confer cardioprotection and inhibit adverse ventricle remodeling. The nanosystem through synergetic works of miRNA and nanozymes provides an effective approach to treating myocardial I/RI.

Heart failure (HF) has emerged as one of the foremost global health threats due to its intricate pathophysiological mechanisms and multifactorial etiology. Adenosine triphosphate (ATP)-induced cell death represents a novel form of regulated cell deaths, marked by cellular energy depletion and metabolic dysregulation stemming from excessive ATP accumulation, identifying its uniqueness compared to other cell death processes modalities such as programmed cell death and necrosis. Growing evidence suggests that ATP-induced cell death (AICD) is predominantly governed by various biological pathways, including energy metabolism, redox homeostasis and intracellular calcium equilibrium. Recent research has shown that AICD is crucial in HF induced by pathological conditions like myocardial infarction, ischemia-reperfusion injury, and chemotherapy. Thus, it is essential to investigate the function of AICD in the pathogenesis of HF, as this may provide a foundation for the development of targeted therapies and novel treatment strategies. This review synthesizes current advancements in understanding the link between AICD and HF, while further elucidating its involvement in cardiac remodeling and HF progression.

Myocardial ischemia-reperfusion injury (MIRI) significantly affects the prognosis of cardiac surgery patients. The anesthetic dexmedetomidine (Dex) has shown protective effects against ischemia-reperfusion injury in cardiomyocytes; however, its exact mechanism remains unclear. In this study, hypoxia/reoxygenation (H/R) and ischemia/reperfusion (I/R) models were used to investigate the effects of Dex on H9c2 cells and MIRI in mice. The roles of the Sirtuin 1/Forkhead box O3a (Sirt1/FoxO3a) pathway in the protective effects of Dex were explored using the Sirt1 inhibitor EX527 and FoxO3a gene silencing. Results showed that H/R significantly reduced H9c2 cell viability, increased Lactate Dehydrogenase (LDH) leakage, and elevated reactive oxygen species (ROS) production. Dex pretreatment reversed these effects. Additionally, Dex significantly reduced the expression of Bcl-2-associated X protein/B-cell lymphoma 2 (Bax/Bcl-2), cleaved caspase-3, Beclin-1, and microtubule-associated protein 1A/1B-light chain 3B (LC3B), inhibiting apoptosis and autophagy while increasing the expression of p62, Sirt1, and FoxO3a. The protective effects of Dex against H/R injury were abolished by EX527 or FoxO3a silencing. In the mouse MIRI model, Dex pretreatment decreased serum LDH and Creatine Kinase-MB (CK-MB) levels, reduced myocardial infarct size and cardiac injury, and significantly improved left ventricular ejection fraction (LVEF) and left ventricular fractional shortening (LVFS). These protective effects were markedly reversed by EX527. These findings indicate that Dex alleviates MIRI by restoring Sirt1 expression and activating FoxO3a.

Ischemia-reperfusion (IR)-induced myocardial damage represents a major pathological event in coronary artery disease (CAD). Effective therapeutic strategies are urgently needed to improve clinical outcomes for CAD patients. Apelin-13, primarily produced by magnocellular neurons, exhibits diverse biological functions across various cell types and tissues. However, its role in myocardial IR injury remains unexplored. In this study, we utilized an in vitro model of myocardial IR injury using H9c2 cardiomyocytes to investigate the potential protective effects of Apelin-13. Our findings reveal that Apelin-13 protects against hypoxia/reoxygenation (H/R)-induced oxidative stress in H9c2 cells by reducing mitochondrial reactive oxygen species (ROS) and malondialdehyde (MDA) levels, while enhancing superoxide dismutase (SOD) activity. Additionally, Apelin-13 alleviates H/R-induced mitochondrial dysfunction, as evidenced by increased mitochondrial membrane potential (MMP) and adenosine triphosphate (ATP) production. Crucially, Apelin-13 mitigates H/R-induced cardiomyocyte injury, as shown by reduced levels of creatine kinase-myocardial band (CK-MB), cardiac troponin I (cTnI), and lactate dehydrogenase (LDH). Remarkably, Apelin-13 also counteracts ferroptosis during H/R by decreasing ferrous iron (Fe²⁺) concentrations, increasing glutathione (GSH) levels, and suppressing glutathione peroxidase 4 (GPX4) and ferritin heavy chain 1 (FTH1) expression. These protective actions were negated by the ferroptosis inducer Erastin. Further investigation revealed that Apelin-13 activates the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) through enhanced nuclear translocation and upregulation of heme oxygenase-1 (HO-1). Conversely, Nrf2 knockdown nullified the protective effects of Apelin-13 against ferroptosis and cardiomyocyte injury, underscoring the critical involvement of Nrf2 in mediating these benefits. Collectively, our results highlight the promising therapeutic potential of Apelin-13 in managing CAD.

Precise and effective management of myocardial ischemia/reperfusion injury (MIRI) is still a formidable challenge in clinical practice. Additionally, real-time monitoring of drug aggregation in the MIRI region remains an open question. Herein, a drug delivery system, hesperadin and ICG assembled in PLGA-Se-Se-PEG-IMTP (HI@PSeP-IMTP), is designed to deliver hesperadin and ICG to the MIRI region for in vivo optical imaging tracking and to ameliorate MIRI. The peak aggregation of nanoprobes in the MIRI region is monitored by near-infrared fluorescence and photoacoustic imaging. The maximal fluorescence and photoacoustic signals of the HI@PSeP-IMTP group in the MIRI region rise ≈32% and 40% respectively compared with that of HI@PSeP group. Moreover, HI@PSeP-IMTP effectively mitigates MIRI due to a synergistic integration of diselenide bonds and hesperadin, which can eliminate ROS and suppress cardiac inflammation. Specifically, the expression levels of p-CaMKII, p-IκBα, and p65 in the MIRI region in the HI@PSeP-IMTP group demonstrate a reduction of 30%, 46%, and 42% respectively compared to that of the PBS group. Collectively, HI@PSeP-IMTP provides new insights into the development of drugs integrating diagnosis and treatment for MIRI.

Cardiovascular diseases (CVDs) represent a leading global health crisis, significantly impairing patients' quality of life and posing substantial risks to their survival. Conventional therapies for CVDs often grapple with challenges such as inadequate targeting precision, suboptimal therapeutic efficacy, and potential adverse side effects. To address these shortcomings, researchers are intensively developing advanced drug delivery systems characterized by high specificity and selectivity, excellent biodegradability, superior biocompatibility, and minimal toxicity. These innovative systems enable the precise delivery of pharmaceuticals with high drug-loading capacities, minimal leakage, and expansive specific surface areas, thereby enhancing therapeutic outcomes. In this review, we summarize and classify various drug delivery materials targeting CVDs and application values. We also evaluate the feasibility and efficacy of viral and non-viral vectors for the treatment of CVDs, the existing limitations and application prospects are also discussed. We hope that this review will provide new perspectives for the future development of drug delivery systems for the treatment of CVDs, ultimately contributing to improved patient care and outcomes.

Mitochondrial dysfunction is a key factor in exacerbating pressure overload-induced cardiac hypertrophy and is linked to increased morbidity and mortality. ECSIT, a crucial adaptor for inflammation and mitochondrial function, has been reported to express multiple transcripts in various species and tissues, leading to distinct protein isoforms with diverse subcellular localizations and functions. However, whether an unknown ECSIT isoform exists in cardiac cells and its potential role in regulating mitochondrial function and pathological cardiac hypertrophy has remained unclear. This study identified a 42-kDa ECSIT isoform encoded by the transcript variant Ecsit-X4, which is highly expressed in the mitochondria of adult cardiomyocytes but down-regulated in hypertrophic human heart samples and TAC-treated mouse hearts. AAV9-mediated Ecsit-X4 gene therapy, administered either before or after TAC surgery, significantly attenuated cardiac hypertrophy. Cardiomyocyte-specific Ecsit deficiency worsened TAC-induced cardiac hypertrophy, while Ecsit-X4 compensation independently rescued hypertrophic phenotypes in EcsitcKO mice. Mechanistically, ECSIT-X4 localized to the mitochondria and interacted with STAT3, leading to increased STAT3 levels and enhanced serine 727 phosphorylation in cardiomyocyte mitochondria, thereby promoting strong mitochondrial bioenergetics. This study identified a novel transcript variant of ECSIT localized in the mitochondria of adult cardiomyocytes and highlights its potential as a therapeutic target for heart failure.

Programmed necrosis/necroptosis greatly contributes to the pathogenesis of cardiac disorders including myocardial infarction, ischemia/reperfusion (I/R) injury and heart failure. However, the fundamental mechanism underlying myocardial necroptosis, especially the mitochondria-dependent death pathway, is poorly understood. Synaptotagmin-1 (Syt1), a Ca2+ sensor, is originally identified in nervous system and mediates synchronous neurotransmitter release. The later findings of Syt1 expressions in many non-neuronal tissues including muscles suggest that Syt1 may exert important functions beyond regulation of neurotransmitter release. Syt1 is highly expressed in cardiomyocytes and has been used as an extracellular molecular probe for SPECT imaging of cardiac cell death in acute myocardial infarction. However, whether Syt1 functions in the pathogenesis of cardiac disorders and what is the molecular etiology have not yet been clarified. We showed here that Syt1 expression was significantly down-regulated in mice I/R injured heart tissues, H2O2-challenged cardiomyocytes and hypoxia/reoxygenation (H/R)-damaged cardiomyocytes. Enforced expression of Syt1 significantly inhibited myocardial necrotic cell death and interstitial fibrosis, and improved cardiac function in mice subjected to I/R operation. In exploring the underlying mechanisms, we found that Syt1 interacted with Parkin and promoted Parkin-catalyzed CypD ubiquitination, thus inhibited mitochondrial membrane permeability transition pore (mPTP) opening and ultimately suppressed cardiomyocyte necrosis. We further found that Syt1 expression was negatively regulated by miR-193b-3p. MiR-193b-3p regulated cardiomyocyte necrosis and mPTP opening by targeting Syt1. Our present work revealed a novel regulatory model of myocardial necrosis composed of miR-193b-3p, Syt1, Parkin, and CypD, which may provide potential therapeutic targets and strategies for heart protection.

Microglial-mediated neuroinflammation is crucial in the pathophysiological mechanisms of secondary brain injury (SBI) following intracerebral hemorrhage (ICH). Mitochondria are central regulators of inflammation, influencing key pathways such as alternative splicing, and play a critical role in cell differentiation and function. Mitochondrial ATP synthase coupling factor 6 (ATP5J) participates in various pathological processes, such as cell proliferation, migration, and inflammation. However, the role of ATP5J in microglial activation and neuroinflammation post-ICH is poorly understood. This study aimed to investigate the effects of ATP5J on microglial activation and subsequent neuroinflammation in ICH and to elucidate the underlying mechanisms. We observed that ATP5J was upregulated in microglia after ICH. AAV9-mediated ATP5J overexpression worsened neurobehavioral deficits, disrupted the blood-brain barrier, and increased brain water content in ICH mice. Conversely, ATP5J knockdown ameliorated these effects. ATP5J overexpression also intensified microglial activation, neuronal apoptosis, and inflammatory responses in surrounding tissues post-ICH. ATP5J impaired microglial dynamics and reduced the proliferation and migration of microglia to injury sites. We used oxyhemoglobin (OxyHb) to stimulate BV2 cells and model ICH in vitro. Further in vitro studies showed that ATP5J overexpression enhanced OxyHb-induced microglial functional transformation. Mechanistically, ATP5J silencing reversed dynamin-related protein 1 (Drp1) and mitochondrial fission 1 protein (Fis1) upregulation in microglia post-OxyHb induction; reduced mitochondrial overdivision, excessive mitochondrial permeability transition pore opening, and reactive oxygen species production; restored normal mitochondrial ridge morphology; and partially restored mitochondrial respiratory electron transport chain activity. ATP5J silencing further alleviated OxyHb-induced mitochondrial dysfunction by regulating mitochondrial metabolism. Our results indicate that ATP5J is a key factor in regulating microglial functional transformation post-ICH by modulating mitochondrial dysfunction and metabolism, thereby positively regulate neuroinflammation. By inhibiting ATP5J, SBI following ICH could be prevented. Therefore, ATP5J could be a candidate for molecular and therapeutic target exploration to alleviate neuroinflammation post-ICH.

Cancer immunotherapy offers significant clinical benefits for patients with advanced or metastatic tumors. However, immunotherapeutic efficacy is often hindered by the tumor microenvironment's high redox levels, leading to variable patient outcomes. Herein, a therapeutic liposomal gold nanocage (MGL) is innovatively developed based on photo-triggered hyperthermia and a releasable strategy by combining a glutathione (GSH) depletion to remodel the tumor immune microenvironment, fostering a more robust anti-tumor immune response. MGL comprises a thermosensitive liposome shell and a gold nanocage core loaded with maleimide. The flexible shell promotes efficient uptake by cancer cells, enabling targeted destruction through photothermal therapy while triggering immunogenic cell death and the maturation of antigen-presenting cells. The photoactivated release of maleimide depletes intracellular GSH, increasing tumor cell sensitivity to oxidative stress and thermal damage. Conversely, GSH reduction also diminishes immunosuppressive cell activity, enhances antigen presentation, and activates T cells. Moreover, photothermal immunotherapy decreases elevated levels of heat shock proteins in tumor cells, further increasing their sensitivity to hyperthermia. In summary, MGL elicited a robust systemic antitumor immune response through GSH depletion, facilitating an effective photothermal immunotherapeutic strategy that reprograms the tumor microenvironment and significantly inhibits primary and metastatic tumors. This approach demonstrates considerable translational potential and clinical applicability.

Oxidative stress, predominantly from neuronal mitochondrial damage and the resultant cytokine storm, is central to cerebral ischemia-reperfusion injury (CIRI). However, delivering drugs to neuronal mitochondria remains challenging due to the blood-brain barrier (BBB), which impedes drug entry into affected brain tissues. This study introduces an innovative tannic acid (TA) and melanin-modified heteropolyacid nanomedicine (MHT), which highly specifically eliminates the neuronal mitochondrial reactive oxygen radicals burst to efficiently reduce neuronal mitochondrial damage through a strategically designed sequential targeting strategy from affected brain tissue to neuronal mitochondria. TA endows MHT with sequential targeting ability by binding to matrix proteins exposed to the damaged BBB and mitochondrial outer membrane proteins of neurons, while melanin significantly enhances the antioxidant capacity of MHT. Consequently, MHT effectively inhibits neuronal apoptosis by protecting mitochondria and reversing the inflammatory immune environment through the deactivation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. MHT demonstrated a strong therapeutic effect on CIRI, with an ultralow dose (2 mg kg-1) proving effective in reversing the condition. This work not only introduces a new avenue to significantly reduce CIRI through sequential targeting therapy but also offers a new paradigm for treating other ischemia-reperfusion injury diseases.

Bacterial biofilm formation is closely associated with persistent infections of medical implants, which can lead to implantation failure. Additionally, the reconstruction of the vascular network is crucial for achieving efficient osseointegration. Herein, an anti-biofilm nanoplatform based on L-arginine (LA)/new indocyanine green (NICG) that is anchored to strontim titanium oxide (SrTiO3) nano-arrays on a titanium (Ti) substrate by introducing polydopamine (PDA) serving as the interlayer is designed and successfully fabricated. Near-infrared light (NIR) is used to excite NICG, generating reactive oxygen species (ROS) that react with LA to release nitric oxide (NO) molecules. Utilizing the concentration-dependent effect of NO, high power density NIR irradiation applied during the early stage after implantation to release a high concentration of NO, which synergized with the photothermal effect of PDA to eliminate bacterial biofilm. Subsequently, the irradiation power density can be finely down-regulated to reduce the NO concentration in subsequent treatment for accelerating the reconstruction of blood vessels. Meanwhile, SrTiO3 nano-arrays improve the hydrophilicity of the implant surface and slowly release strontium (Sr) ions for continuously optimizing the osteogenic microenvironment. Effective biofilm elimination and revascularization alongside the continuous optimization of the osteogenic microenvironment can significantly enhance the osseointegration of the functionalized Ti implant in in vivo animal experiments.

Myocardial ischemia/reperfusion (MI/R) injury, a major contributor to poor prognosis in patients with acute myocardial infarction, currently lacks effective therapeutic strategies in clinical practice. The long noncoding RNA (lncRNA) Oip5-as1 can regulate various cellular processes, such as cell proliferation, differentiation, and survival. Oip5-as1 may have potential as a therapeutic target for MI/R injury as its upregulated expression has been associated with reduced infarct size and improved cardiac function in animal models, although how to effectively and safely overexpress Oip5-as1 in vivo remains unclear. Lipid nanoparticles (LNPs) are a versatile technology for targeted drug delivery in numerous therapeutic applications. Herein, we aimed to assess the therapeutic efficacy and safety of LNPs coloaded with Oip5-as1 and a cardiomyocyte-specific binding peptide (LNP@Oip5-as1@CMP) in a murine model of MI/R injury. To achieve this, LNP@Oip5-as1@CMP was synthesized via ethanol injection method. The structural components of LNP@Oip5-as1@CMP were physicochemically analyzed. A hypoxia/reoxygenation (H/R) model in HL-1 cells and coronary artery ligation in mice were used to simulate MI/R injury. Our results demonstrated that LNPs designed for cardiomyocyte targeting and efficient Oip5-as1 delivery were successfully synthesized. In HL-1 cells, LNP@Oip5-as1@CMP treatment significantly reduced mitochondrial apoptosis caused by H/R injury. In the murine MI/R model, the intravenous administration of LNP@Oip5-as1@CMP significantly decreased myocardial infarct size and improved cardiac function. Mechanistic investigations revealed that Oip5-as1 delivery inhibited the p53 signaling pathway. However, the cardioprotective effects of Oip5-as1 were abrogated by administrating Nutlin-3a, a p53 activator. Furthermore, no signs of major organ damage were detected after LNP@Oip5-as1@CMP injection. Our study reveals the therapeutic potential of LNPs for targeted Oip5-as1 delivery in mitigating MI/R injury. These findings pave the way for advanced targeted treatments in cardiovascular diseases, emphasizing the promise of lncRNA-based therapies.

Myocardial ischemia-reperfusion injury (MI/RI) is an unavoidable risk event for acute myocardial infarction, with ferroptosis showing close involvement. We investigated the mechanism of MI/RI inducing myocardial injury by inhibiting the ferroptosis-related SLC7A11/glutathione (GSH)/glutathione peroxidase 4 (GPX4) pathway and activating mitophagy.

A rat MI/RI model was established, with myocardial infarction area and injury assessed by TTC and H&E staining. Rat cardiomyocytes H9C2 were cultured in vitro, followed by hypoxia/reoxygenation (H/R) modeling and the ferroptosis inhibitor lipoxstatin-1 (Lip-1) treatment, or 3-Methyladenine or rapamycin treatment and overexpression plasmid (oe-SLC7A11) transfection during modeling. Cell viability and death were evaluated by CCK-8 and LDH assays. Mitochondrial morphology was observed by transmission electron microscopy. Mitochondrial membrane potential was detected by fluorescence dye JC-1. Levels of inflammatory factors, reactive oxygen species (ROS), Fe2+, malondialdehyde, lipid peroxidation, GPX4 enzyme activity, glutathione reductase, GSH and glutathione disulfide, and SLC7A11, GPX4, LC3II/I and p62 proteins were determined by ELISA kit, related indicator detection kits and Western blot.

The ferroptosis-related SLC7A11/GSH/GPX4 pathway was repressed in MI/RI rat myocardial tissues, inducing myocardial injury. H/R affected GSH synthesis and inhibited GPX4 enzyme activity by down-regulating SLC7A11, thus promoting ferroptosis in cardiomyocytes, which was averted by Lip-1. SLC7A11 overexpression improved H/R-induced cardiomyocyte ferroptosis via the GSH/GPX4 pathway. H/R activated mitophagy in cardiomyocytes. Mitophagy inhibition reversed H/R-induced cellular ferroptosis. Mitophagy activation partially averted SLC7A11 overexpression-improved H/R-induced cardiomyocyte ferroptosis. H/R suppressed the ferroptosis-related SLC7A11/GSH/GPX4 pathway by inducing mitophagy, leading to cardiomyocyte injury.

Increased ROS under H/R conditions triggered cardiomyocyte injury by inducing mitophagy to suppress the ferroptosis-related SLC7A11/GSH/GPX4 signaling pathway activation.

Doxorubicin (Dox) is a broad-spectrum antineoplastic chemotherapeutic agent used in clinical settings, yet it exhibits significant cardiotoxicity, which in severe cases can lead to heart failure. Research indicates that oxidative stress plays a pivotal role in Dox -induced cardiomyocyte injury. Therefore, the application of antioxidants represents an effective strategy to mitigate the cardiotoxic effects of doxorubicin. In preliminary studies, we isolated an antioxidative peptide, PHWWEYRR (8P). This study utilizes a PCM cardiomyocyte-targeting peptide-modified liposome as a carrier to deliver 8P into cardiomyocytes, aiming to prevent Dox-induced cardiac injury through its antioxidative mechanism. The results demonstrated that we prepared the 8P-loaded and PCM-targeting peptide-modified liposome (P-P-8P), which exhibited good dispersibility, encapsulation efficiency, drug loading capacity, and in vitro release, along with myocardial targeting capability. In vitro experiments showed that P-P-8P could prevent oxidative stress injury in H9C2 cells, protect mitochondrial functions, and inhibit cell apoptosis through a mitochondria-dependent pathway. In vivo experiments indicated that P-P-8P could prevent abnormalities in serum biochemical indicators, cardiac dysfunction, and myocardial pathological changes in mice. In conclusion, P-P-8P effectively delivers 8P to cardiomyocytes, offering protection against the cardiotoxic effects of Dox, and holds potential as a future preventative or therapeutic agent for drug-induced cardiomyopathy.

This study aims to systematically analyze the potential active components of Eucommiae cortex in the treatment of post- myocardial infarction heart failure through network analysis and molecular docking methods. In vitro experiments were conducted to verify that medioresinol, a component of Eucommiae cortex, improves oxygen-glucose deprivation-induced cell failure through its anti-inflammatory and antioxidant capacities.

Potential active components of Eucommiae cortex were screened using specific data. The targets of these components were predicted using Swiss Institute of Bioinformatics database and TargetNet, and key targets were identified by intersecting with the disease targets of myocardial infarction and heart failure. Protein-Protein Interaction analysis was performed on the key targets to screen for core targets. Genomics Institute of the Novartis Research Foundation and Human Protein Atlas were used to identify myocardial highly expressed targets. Kyoto Encyclopedia of Genes and Genomes and Gene Ontology enrichment analyses were conducted using the Database for Annotation, Visualization, and Integrated Discovery. Molecular docking was performed for the final components and target proteins. In vitro experiments were carried out using H9c2 cells subjected to oxygen and glucose deprivation conditions to validate the effects of the screened potential active components.

Network analysis revealed that Eucommiae cortex might exert its effects through the phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), hypoxia-inducible factor 1, and Janus kinase/signal transducer and activator of transcription pathways, which are crucial for myocardial contraction, vascular tone regulation, inflammatory response, and oxidative stress. Molecular docking indicated stable binding of the selected compounds to PI3K, AKT, and mTOR. Medioresinol was selected for further study and shown to significantly improve oxidative stress and inflammatory response in myocardial ischemia-hypoxia model cells by activating the PI3K/AKT/mTOR pathway.

This study confirms the role of the PI3K/AKT/mTOR pathway in the cardiovascular protective effects of Eucommiae cortex and provides evidence at the cellular level. Medioresinol demonstrated potential therapeutic effects on myocardial infarction induced heart failure by reducing oxidative stress and inflammatory responses. These findings offer a theoretical basis for the application of Eucommiae cortex in the treatment of heart failure and support the development of new therapeutic drugs for cardiovascular diseases. Future research should further validate these effects in animal models and explore the overall efficacy of Eucommiae cortex.

Ischemic heart disease (IHD) is increasingly recognized as a significant cardiovascular disease with a growing global incidence. Interventions targeting the oxidative microenvironment have long been pivotal in therapeutic strategies. However, many antioxidant drugs face limitations due to pharmacokinetic and delivery challenges, such as short half-life, poor stability, low bioavailability, and significant side effects. Fortunately, nanotherapies exhibit considerable potential in addressing IHD. Nanomedicines offer advantages such as passive/active targeting, prolonged circulation time, enhanced bioavailability, and diverse carrier options. This comprehensive review explores the advancements in nanomedicines for mitigating IHD through oxidative stress regulation, providing an extensive overview for researchers in the field of antioxidant nanomedicines. By inspiring further research, this study aims to accelerate the development of novel therapies for myocardial injury.

Vascular injury is central to the pathogenesis and progression of cardiovascular diseases, however, fostering alternative strategies to alleviate vascular injury remains a persisting challenge. Given the central role of cell-derived nitric oxide (NO) in modulating the endogenous repair of vascular injury, NO-generating proteolipid nanovesicles (PLV-NO) are designed that recapitulate the cell-mimicking functions for vascular repair and replacement. Specifically, the proteolipid nanovesicles (PLV) are versatilely fabricated using membrane proteins derived from different types of cells, followed by the incorporation of NO-generating nanozymes capable of catalyzing endogenous donors to produce NO. Taking two vascular injury models, two types of PLV-NO are tailored to meet the individual requirements of targeted diseases using platelet membrane proteins and endothelial membrane proteins, respectively. The platelet-based PLV-NO (pPLV-NO) demonstrates its efficacy in targeted repair of a vascular endothelium injury model through systemic delivery. On the other hand, the endothelial cell (EC)-based PLV-NO (ePLV-NO) exhibits suppression of thrombosis when modified onto a locally transplanted small-diameter vascular graft (SDVG). The versatile design of PLV-NO may enable a promising therapeutic option for various vascular injury-evoked cardiovascular diseases.

Vascular diseases seriously threaten human life and health. Exogenous delivery of nitric oxide (NO) represents an effective approach for maintaining vascular homeostasis during pathological events. However, the overproduction of reactive oxygen species (ROS) at vascular injury sites would react with NO to produce damaging peroxynitrite (ONOO-) species and limit the therapeutic effect of NO. Hence, we design a ROS-responsive NO nanomedicine (t-PBA&NO NP) with ROS scavenging ability to solve the dilemma of NO-based therapy. t-PBA&NO NP targets NO and anti-oxidant ethyl caffeate (ECA) to the injury sites via collagen IV homing peptide. The ROS-triggered ROS depletion and ECA release potently alleviate local oxidative stress via ROS scavenging, endoplasmic reticulum and mitochondrial regulation. It subsequently maximizes vascular modulation effects of NO, without production of harmful compounds, reactive nitrogen species (RNS). Therefore, it significantly increases competitiveness of human umbilical vein endothelial cells (HUVECs) over human aortic smooth muscle cells (HASMCs) both in vitro and in vivo. The strategy proved effective in inducing faster re-endothelialization, inhibiting neointimal formation and restoring vascular homeostasis. The synergy between ROS depletion and NO therapy served as a new inspiration for the treatment of cardiovascular diseases and other ROS-associated illnesses.

Myocardial infarction, usually caused by the rupture of atherosclerotic plaque, leads to irreversible ischemic cardiomyocyte death within hours followed by impaired cardiac performance or even heart failure. Current interventional reperfusion strategies for myocardial infarction still face high mortality with the development of heart failure. Nanomaterial-based therapy has made great progress in reducing infarct size and promoting cardiac repair after MI, although most studies are preclinical trials. This review focuses primarily on recent progress (2016-now) in the development of various nanomedicines in the treatment of myocardial infarction. We summarize these applications with the strategy of mechanism including anti-cardiomyocyte death strategy, activation of neovascularization, antioxidants strategy, immunomodulation, anti-cardiac remodeling, and cardiac repair.

Ischemia/reperfusion (I/R) injury significantly contributes to the morbidity and mortality associated with cardiac events. Poloxamer 188 (P188), a nonionic triblock copolymer, has been proposed to mitigate I/R injury by stabilizing cell membranes. However, the underlying mechanisms remain incompletely understood, particularly concerning endothelial cell function and nitric oxide (NO) production. We employed human induced pluripotent stem cell (iPSC)-derived cardiomyocytes (CMs) and endothelial cells (ECs) to elucidate the effects of P188 on cellular survival, function, and NO secretion under simulated I/R conditions. iPSC-CMs contractility and iPSC-ECs' NO production were assessed following exposure to P188. Further, an isolated heart model using Brown Norway rats subjected to I/R injury was utilized to evaluate the ex-vivo cardioprotective effects of P188, examining cardiac function and NO production, with and without the administration of a NO inhibitor. In iPSC-derived models, P188 significantly preserved CM contractile function and enhanced cell viability after hypoxia/reoxygenation. Remarkably, P188 treatment led to a pronounced increase in NO secretion in iPSC-ECs, a novel finding demonstrating endothelial protective effects beyond membrane stabilization. In the rat isolated heart model, administration of P188 during reperfusion notably improved cardiac function and reduced I/R injury markers. This cardioprotective effect was abrogated by NO inhibition, underscoring the pivotal role of NO. Additionally, a dose-dependent increase in NO production was observed in non-ischemic rat hearts treated with P188, further establishing the critical function of NO in P188 induced cardioprotection. In conclusion, our comprehensive study unveils a novel role of NO in mediating the protective effects of P188 against I/R injury. This mechanism is evident in both cellular models and intact rat hearts, highlighting the potential of P188 as a therapeutic agent against I/R injury. Our findings pave the way for further investigation into P188's therapeutic mechanisms and its potential application in clinical settings to mitigate I/R-related cardiac dysfunction.

The potential effects of short-term exposure to major ambient gaseous pollutants (ozone: O3, carbon monoxide: CO, and sulfur dioxide: SO2) on platelet mitochondrial DNA (mtDNA) methylation have been uncertain and no studies have examined whether platelet mtDNA methylation levels could modify the associations between ambient gaseous pollutants and the risks of ST-segment depression (STDE) and T-wave inversion events (TIE), two indicators of myocardial ischemia.

This study used data from a randomized, double-blind, placebo-controlled intervention study with a standardized 24-hour exposure protocol among 110 participants in Beijing. Absolute changes in platelet mtDNA methylation (ACmtDNAm) levels were determined by two repeated measurements on platelet mtDNA methylation levels in blood samples collected before and after the 24-hour exposure period. A multivariable linear regression model and a generalized linear model with a Poisson link function were used to investigate the associations of ambient gaseous pollutants with platelet mtDNA methylation levels, STDE, and TIE, respectively.

Short-term O3 exposure was significantly associated with decreased ACmtDNAm at ATP6_P1 but increased ACmtDNAm at mt12sRNA, MT-COX1, and MT-COX1_P2; short-term CO and SO2 exposures were significantly associated with decreased ACmtDNAm at D-loop, MT-COX3- and ATP-related genes. Moreover, short-term O3 exposure was significantly associated with increased risks of STDE and TIE, and ACmtDNAm at MT-COX1 and MT-COX1_P2 modified the association between short-term O3 exposure and STDE events. L-Arg supplementation attenuated the effects of ambient gaseous pollutants, particularly O3, on ACmtDNAm and STDE.

Platelet mtDNA methylation levels are promising biomarkers of short-term exposure to ambient gaseous air pollution, and are likely implicated in the mechanism behind the association of ambient O3 pollution with adverse cardiovascular effects. L-Arg supplementation showed the potential to mitigate the adverse effects of ambient O3 pollution.

MicroRNA (miRNA)-based therapies have shown great potential in myocardial repair following myocardial infarction (MI). MicroRNA-302 (miR302) has been reported to exert a protective effect on MI. However, miRNAs are easily degraded and ineffective in penetrating cells, which limit their clinical applications. Exosomes, which are small bioactive molecules, have been considered as an ideal vehicle for miRNAs delivery due to their cell penetration, low immunogenicity and excellent stability potential. Herein, we explored cardiomyocyte-targeting exosomes as vehicles for delivery of miR302 into cardiomyocyte to potentially treat MI.

To generate an efficient exosomal delivery system that can target cardiomyocytes, we engineered exosomes with cardiomyocyte specific peptide (CMP, WLSEAGPVVTVRALRGTGSW). Afterwards, the engineered exosomes were characterized and identified using transmission electron microscope (TEM) and Nanoparticle Tracking Analysis (NTA). Later on, the miR302 mimics were loaded into the engineered exosomes via electroporation technique. Subsequently, the effect of the engineered exosomes on myocardial ischemia and reperfusion (I/R) injury was evaluated in vitro and in vivo, including MTT, ELISA, real-time quantitative polymerase chain reaction (PCR), western blot, TUNNEL staining, echocardiogram and hematoxylin and eosin (HE) staining.

Results of in vitro experimentation showed that DSPE-PEG-CMP-EXO could be more efficiently internalized by H9C2 cells than unmodified exosomes (blank-exosomes). Importantly, compared with the DSPE-PEG-CMP-EXO group, DSPE-PEG-CMP-miR302-EXO significantly upregulated the expression of miR302, while exosomes loaded with miR302 could enhance proliferation of H9C2 cells. Western blot results showed that the DSPE-PEG-CMP-miR302-EXO significantly increased the protein level of Ki67 and Yap, which suggests that DSPE-PEG-CMP-miR302-EXO enhanced the activity of Yap, the principal downstream effector of Hippo pathway. In vivo, DSPE-PEG-CMP-miR302-EXO improved cardiac function, attenuated myocardial apoptosis and inflammatory response, as well as reduced infarct size significantly.

In conclusion, our findings suggest that CMP-engineered exosomes loaded with miR302 was internalized by H9C2 cells, an in vitro model for cardiomyocytes coupled with potential enhancement of the therapeutic effects on myocardial I/R injury.

Nuclear factor erythroid-2 related factor 2 (Nrf2), a nuclear transcription factor, modulates genes responsible for antioxidant responses against toxic and oxidative stress to maintain redox homeostasis and participates in varieties of cellular processes such as metabolism and inflammation during myocardial ischemia and reperfusion injuries (MIRI). The accumulation of reactive oxygen species (ROS) from damaged mitochondria, xanthine oxidase, NADPH oxidases, and inflammation contributes to depraved myocardial ischemia and reperfusion injuries. Considering that Nrf2 played crucial roles in antagonizing oxidative stress, it is reasonable to delve into the up or down-regulated molecular mechanisms of Nrf2 in the progression of MIRI to provide the possibility of new therapeutic medicine targeting Nrf2 in cardiovascular diseases. This review systematically describes the generation of ROS, the regulatory metabolisms of Nrf2 as well as several natural or synthetic compounds activating Nrf2 during MIRI, which might provide novel insights for the anti-oxidative stress and original ideas targeting Nrf2 for the prevention and treatment in cardiovascular diseases.

Despite significant strides in prevention, diagnosis, and treatment, cardiovascular diseases remain the number one cause of mortality in the United States, with rates climbing at an alarming rate in the developing world. Targeted delivery of therapeutics to the heart has been a lofty goal to achieve with strategies ranging from direct intra-cardiac or intra-pericardial delivery, intra-coronary infusion, to adenoviral, lentiviral, and adeno-associated viral vectors which have preference, if not complete cardio-selectivity, for cardiac tissue. Cell-penetrating peptides (CPP) are 5-30-amino-acid-long peptides that are able to breach cell membrane barriers while carrying cargoes up to several times their size, in an intact functional form. Identified nearly three decades ago, the first of these CPPs came from the HIV coat protein transactivator of transcription. Although a highly efficient CPP, its clinical utility is limited by its robust ability to cross any cell membrane barrier, including crossing the blood-brain barrier and transducing neuronal tissue non-specifically. Several strategies have been utilized to identify cell- or tissue-specific CPPs, one of which is phage display. Using this latter technique, we identified a cardiomyocyte-targeting peptide (CTP) more than a decade ago, a finding that has been corroborated by several independent labs across the world that have utilized CTP for a myriad of different purposes in pre-clinical animal models. The goal of this publication is to provide a comprehensive review of the identification, validation, and application of CTP, and outline its potential in diagnostic and therapeutic applications especially in the field of targeted RNA interference.

Nanotechnology, an emerging force, has infiltrated diverse domains like biomedical, materials, and environmental sciences. Nano-omics, an emerging fusion, combines nanotechnology with omics, boasting amplified sensitivity and resolution. This review introduces nanotechnology basics, surveys its recent strides in nano-omics, deliberates present challenges, and envisions future growth.

Myocardial ischemic reperfusion injury (MIRI) is a crucial clinical problem globally. The molecular mechanisms of MIRI need to be fully explored to develop new therapeutic methods. Galangin (Gal), which is a natural flavonoid extracted from Alpinia Officinarum Hance and Propolis, possesses a wide range of pharmacological activities, but its effects on MIRI remain unclear. This study aimed to determine the pharmacological effects of Gal on MIRI.

C57BL/6 mice underwent reperfusion for 3 h after 45 min of ischemia, and neonatal rat cardiomyocytes (NRCs) subjected to hypoxia and reoxygenation (HR) were cultured as in vivo and in vitro models. Echocardiography and TTC-Evans Blue staining were performed to evaluate the myocardial injury. Transmission electron microscope and JC-1 staining were used to validate the mitochondrial function. Additionally, Western blot detected ferroptosis markers, including Gpx4, FTH, and xCT.

Gal treatment alleviated cardiac myofibril damage, reduced infarction size, improved cardiac function, and prevented mitochondrial injury in mice with MIRI. Gal significantly alleviated HR-induced cell death and mitigated mitochondrial membrane potential reduction in NRCs. Furthermore, Gal significantly inhibited ferroptosis by preventing iron overload and lipid peroxidation, as well as regulating Gpx4, FTH, and xCT expression levels. Moreover, Gal up-regulated nuclear transcriptive factor Nrf2 in HR-treated NRCs. Nrf2 inhibition by Brusatol abolished the protective effect of Gal against ferroptosis.

This study revealed that Gal alleviates myocardial ischemic reperfusion-induced ferroptosis by targeting Nrf2/Gpx4 signaling pathway.