Single-Atom-Based Nanoenzyme in Tissue Repair.

Since the discovery of ferromagnetic nanoparticles Fe3O4 that exhibit enzyme-like activity in 2007, the research on nanoenzymes has made significant progress. With the in-depth study of various nanoenzymes and the rapid development of related nanotechnology, nanoenzymes have emerged as a promising alternative to natural enzymes. Within nanozymes, there is a category of metal-based single-atom nanozymes that has been rapidly developed due to low cast, convenient preparation, long storage, less immunogenicity, and especially higher efficiency. More importantly, single-atom nanozymes possess the capacity to scavenge reactive oxygen species through various mechanisms, which is beneficial in the tissue repair process. Herein, this paper systemically highlights the types of metal single-atom nanozymes, their catalytic mechanisms, and their recent applications in tissue repair. The existing challenges are identified and the prospects of future research on nanozymes composed of metallic nanomaterials are proposed. We hope this review will illuminate the potential of single-atom nanozymes in tissue repair, encouraging their sequential clinical translation.

Advances in local drug delivery technologies for improved rheumatoid arthritis therapy.

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by an inflammatory microenvironment and cartilage erosion within the joint cavity. Currently, antirheumatic agents yield significant outcomes in RA treatment. However, their systemic administration is limited by inadequate drug retention in lesion areas and non-specific tissue distribution, reducing efficacy and increasing risks such as infection due to systemic immunosuppression. Development in local drug delivery technologies, such as nanostructure-based and scaffold-assisted delivery platforms, facilitate enhanced drug accumulation at the target site, controlled drug release, extended duration of the drug action, reduced both dosage and administration frequency, and ultimately improve therapeutic outcomes with minimized damage to healthy tissues. In this review, we introduced pathogenesis and clinically used therapeutic agents for RA, comprehensively summarized locally administered nanostructure-based and scaffold-assisted drug delivery systems, aiming at improving the therapeutic efficiency of RA by alleviating the inflammatory response, preventing bone erosion and promoting cartilage regeneration. In addition, the challenges and future prospects of local delivery for clinical translation in RA are discussed.

Nobiletin alleviates cisplatin-induced ototoxicity via activating autophagy and inhibiting NRF2/GPX4-mediated ferroptosis.

Nobiletin, a citrus polymethoxy flavonoid with antiapoptotic and antioxidative properties, could safeguard against cisplatin-induced nephrotoxicity and neurotoxicity. Cisplatin, as the pioneer of anti-cancer drug, the severe ototoxicity limits its clinical applications, while the effect of nobiletin on cisplatin-induced ototoxicity has not been identified. The current study investigated the alleviating effect of nobiletin on cisplatin-induced ototoxicity and the underlying mechanisms. Apoptosis and ROS formation were evaluated using the CCK-8 assay, Western blotting, and immunofluorescence, indicating that nobiletin attenuated cisplatin-induced apoptosis and oxidative stress. LC3B and SQSTM1/p62 were determined by Western blotting, qPCR, and immunofluorescence, indicating that nobiletin significantly activated autophagy. Nobiletin promoted the nuclear translocation of NRF2 and the transcription of its target genes, including Hmox1, Nqo1, and ferroptosis markers (Gpx4, Slc7a11, Fth, and Ftl), thereby inhibiting ferroptosis. Furthermore, RNA sequencing analysis verified that autophagy, ferroptosis, and the NRF2 signaling pathway served as crucial points for the protection of nobiletin against ototoxicity caused by cisplatin. Collectively, these results indicated, for the first time, that nobiletin alleviated cisplatin-elicited ototoxicity through suppressing apoptosis and oxidative stress, which were attributed to the activation of autophagy and the inhibition of NRF2/GPX4-mediated ferroptosis. Our study suggested that nobiletin could be a prospective agent for preventing cisplatin-induced hearing loss.

Chicoric Acid Ameliorated Beta-Amyloid Pathology and Enhanced Expression of Synaptic-Function-Related Markers via L1CAM in Alzheimer's Disease Models.

Alzheimer's disease (AD) is the most common progressive neurodegenerative disease. The accumulation of amyloid-beta (Aß) plaques is a distinctive pathological feature of AD patients. The aims of this study were to evaluate the therapeutic effect of chicoric acid (CA) on AD models and to explore its underlying mechanisms. APPswe/Ind SH-SY5Y cells and 5xFAD mice were treated with CA. Soluble Aß1-42 and Aß plaque levels were analyzed by ELISA and immunohistochemistry, respectively. Transcriptome sequencing was used to compare the changes in hippocampal gene expression profiles among the 5xFAD mouse groups. The specific gene expression levels were quantified by qRT-PCR and Western blot analysis. It was found that CA treatment reduced the Aß1-42 levels in the APPswe/Ind cells and 5xFAD mice. It also reduced the Aß plaque levels as well as the APP and BACE1 levels. Transcriptome analysis showed that CA affected the synaptic-plasticity-related genes in the 5xFAD mice. The levels of L1CAM, PSD-95 and synaptophysin were increased in the APPswe/Ind SH-SY5Y cells and 5xFAD mice treated with CA, which could be inhibited by administering siRNA-L1CAM to the CA-treated APPswe/Ind SH-SY5Y cells. In summary, CA reduced Aß levels and increased the expression levels of synaptic-function-related markers via L1CAM in AD models.

An injectable cartilage-coating composite with long-term protection, effective lubrication and chondrocyte nourishment for osteoarthritis treatment.

The osteoarthritic (OA) environment within articular cartilage poses significant challenges, resulting in chondrocyte dysfunction and cartilage matrix degradation. While intra-articular injections of anti-inflammatory drugs, biomaterials, or bioactive agents have demonstrated some effectiveness, they primarily provide temporary relief from OA pain without arresting OA progression. This study presents an injectable cartilage-coating composite, comprising hyaluronic acid and decellularized cartilage matrix integrated with specific linker polymers. It enhances the material retention, protection, and lubrication on the cartilage surface, thereby providing an effective physical barrier against inflammatory factors and reducing the friction and shear force associated with OA joint movement. Moreover, the composite gradually releases nutrients, nourishing OA chondrocytes, aiding in the recovery of cellular function, promoting cartilage-specific matrix production, and mitigating OA progression in a rat model. Overall, this injectable cartilage-coating composite offers promising potential as an effective cell-free treatment for OA. STATEMENT OF SIGNIFICANCE: Osteoarthritis (OA) in the articular cartilage leads to chondrocyte dysfunction and cartilage matrix degradation. This study introduces an intra-articular injectable composite material (HDC), composed of decellularized cartilage matrix (dECMs), hyaluronan (HA), and specially designed linker polymers to provide an effective cell-free OA treatment. The linker polymers bind HA and dECMs to form an integrated HDC structure with an enhanced degradation rate, potentially reducing the need for frequent injections and associated trauma. They also enable HDC to specifically coat the cartilage surface, forming a protective and lubricating layer that enhances long-term retention, acts as a barrier against inflammatory factors, and reduces joint movement friction. Furthermore, HDC nourishes OA chondrocytes through gradual nutrient release, aiding cellular function recovery, promoting cartilage-specific matrix production, and mitigating OA progression.

PM2.5 exposure-induced senescence-associated secretory phenotype in airway smooth muscle cells contributes to airway remodeling.

Fine particulate matter (PM2.5) has been linked to increased severity and incidence of airway diseases, especially chronic obstructive pulmonary disease (COPD) and asthma. Airway remodeling is an important event in both COPD and asthma, and airway smooth muscle cells (ASMCs) are key cells which directly involved in airway remodeling. However, it was unclear how PM2.5 affected ASMCs. This study investigates the effects of PM2.5 on airway smooth muscle and its mechanism. We first showed that inhaled particulate matter was distributed in the airway smooth muscle bundle, combined with increased airway smooth muscle bundle and collagen deposition in vivo. Then, we demonstrated that PM2.5 induced up-regulation of collagen-I and alpha-smooth muscle actin (α-SMA) expression in rat and human ASMCs in vitro. Next, we found PM2.5 led to rat and human ASMCs senescence and exhibited senescence-associated secretory phenotype (SASP) by autophagy-induced GATA4/TRAF6/NF-κB signaling, which contributed to collagen-I and α-SMA synthesis as well as airway smooth muscle remodeling. Together, our results provided evidence that SASP induced by PM2.5 in airway smooth muscle cells prompted airway remodeling.

4-octyl itaconate alleviates cisplatin-induced ferroptosis possibly via activating the NRF2/HO-1 signalling pathway.

Ferroptosis, characterized by iron-dependent lipid reactive oxygen species (ROS) accumulation, plays a pivotal role in cisplatin-induced ototoxicity. Existing research has suggested that in cisplatin-mediated damage to auditory cells and hearing loss, ferroptosis is partially implicated. 4-Octyl itaconate (4-OI), derived from itaconic acid, effectively permeates cell membranes, showcasing potent anti-inflammatory as well as antioxidant effects in several disease models. Our study aimed to investigate the effect of 4-OI on cisplatin-induced ferroptosis and the underlying molecular mechanisms. The survival rates of HEI-OC1 cells and mice cochlea hair cells were measured by CCK8 and immunofluorescence, respectively. The auditory brainstem response (ABR) audiometry was used to detect changes in hearing thresholds in mice before and after treatment. Levels of ROS were evaluated by DCFH-DA. Real-time PCR quantified inflammatory cytokines TNF-α, IL-6 and IL-1ß. Network Pharmacology and RNA sequencing (RNA-seq) analysis of the potential mechanism of 4-OI resistance to cisplatin-induced ferroptosis. The expressions of ferroptosis-related factors (GPX4, SLC7A11 and PTGS2) and important antioxidant factors (NRF2, HO-1, GCLC and NQO1) were tested by real-time PCR, Western blot and immunofluorescence. Results demonstrated cisplatin-induced significant ROS and inflammatory factor release, reduced NRF2 expression, hindered nuclear translocation and activated ferroptosis. Pretreatment with 4-OI exhibited anti-inflammatory and antioxidant effects, along with resistance to ferroptosis, ultimately mitigating cisplatin-induced cell loss. In the present study, we show that 4-OI inhibits cisplatin-induced ferroptosis possibly through activation of the NRF2/HO-1 signalling pathway, thereby exerting a protective effect against cisplatin-induced damage to auditory cells, and providing a new therapeutic strategy for cisplatin-induced hearing loss.

Wearable Microneedle Patch for Colorimetric Detection of Multiple Signature Biomarkers in vivo Toward Diabetic Diagnosis.

Type 2 diabetes is rapidly emerging as a global public health problem. While blood glucose monitoring has been the primary method of managing diabetes for decades, the increasing global prevalence of the disease suggests that there might be a need to identify additional biomarkers for a more precise early diagnosis. Herein, a microneedle patch based wearable sensor is developed for the purpose of diabetic diagnosis. Utilizing methacrylic acid modified gelatin and polyvinyl alcohol in the fabrication of microneedles has improved their mechanical properties for skin penetration and increased swelling capacity for interstitial fluid extraction, thanks to the double crosslinking mechanism. The fabricated microneedles are further integrated with test paper functionalized with enzyme and dye molecules to detect multiple signature biomarkers of diabetes in vivo through a colorimetric reaction. Such a wearable microneedle patch  holds significant promise for the real-time monitoring of various biomarkers related to chronic diseases and aging.

Inhibition of Alzheimer's disease by 4-octyl itaconate revealed by RNA-seq transcriptome analysis.

AIMS: This study aimed to examine the therapeutic effects and response mechanisms of 4-OI in Alzheimer's disease (AD). METHODS: In this study, network pharmacology was employed to analyze potential targets for AD drug therapy. Immunofluorescence and quantitative reverse transcription polymerase chain reaction (qRT-PCR) techniques were utilized to detect inflammatory phenotypes in a 4-OI-resistant mouse microglia cell line (BV2). We conducted four classical behavioral experiments, namely the open field test, new object recognition test, Y maze test, and Morris water maze, to assess the emotional state and cognitive level of APPswe/PS1dE9 (referred to as APP/PS1) mice after 4-OI treatment. Hematoxylin and eosin (HE) staining, along with immunofluorescence staining, were performed to detect amyloid (Aß) deposition in mouse brain tissue. To explore the potential molecular mechanisms regulating the effects of 4-OI treatment, we performed RNA-SEQ and transcription factor prediction analyses. Additionally, mouse BV2 cells underwent Western blotting analysis to elucidate potential molecular mechanisms underlying the observed effects. RESULTS: We discovered that 4-OI exerts an inhibitory effect on neuroinflammation by promoting autophagy. This effect is attributed to the activation of the AMPK/mTOR/ULK1 pathway, achieved through enhanced phosphorylation of AMPK and ULK1, coupled with a reduction in mTOR phosphorylation. Furthermore, 4-OI significantly enhances neuronal recovery in the hippocampus and diminishes Aß plaque deposition in APP/PS1 mice, improved anxiety in mice, and ultimately led to improved cognitive function. CONCLUSIONS: Overall, the results of this study demonstrated that 4-OI improved cognitive deficits in AD mice, confirming the therapeutic effect of 4-OI on AD.

The Value of Computed Tomography in Differentiating Heterotopic Pancreas from Small Gastrointestinal Stromal Tumor.

BACKGROUND: It is critical for an accurate preoperative diagnosis of heterotopic pancreas (HP) and small gastrointestinal stromal tumor (GIST), given the unique treatment and prognosis of the two tumors. This study aims to investigate HP's computed tomography (CT) features and identify the distinguishing characteristics between HP and small GIST. METHODS: From January 2016 to August 2020, our hospital database was searched for confirmed histopathological results and CT scans for HP and GIST for further analysis. The statistically significant variables were determined by using Fisher's exact test, the Mann-Whitney U test, the receiver operating characteristic (ROC) curve and the inverse probability weighting method. RESULTS: CT images and clinical data were reviewed for 24 participants with HP and 34 patients with small GIST. Contour, border, relative enhancement grade, surface dimple, duct-like structure, short diameter (SD), attenuation of each lesion in the unenhanced phase (Lp), and the enhancement ratio of tumor in the venous phase (ER) were significant for differentiating HP from small GIST. Threshold values for SD and Lp were 1.40 cm and 42.33 Hounsfield units, respectively. Ill-defined border, surface dimple, ductlike structure, and Lp were independent factors that differentiated HP from small GIST. Additionally, SD and ER were also found to be independent factors. CONCLUSIONS: Contour, relative enhancement grade, SD, and Lp could effectively differentiate HP from small GIST, demonstrating improved diagnostic performance compared to other parameters. The presence of ductlike structures and surface dimples could further characterize HP. These findings may help distinguish HP from small GIST and avoid unnecessary invasive examination and therapy in individuals with asymptomatic HP.

Injectable Microgels with Hybrid Exosomes of Chondrocyte-Targeted FGF18 Gene-Editing and Self-Renewable Lubrication for Osteoarthritis Therapy.

Abnormal silencing of fibroblast growth factor (FGF) signaling significantly contributes to joint dysplasia and osteoarthritis (OA); However, the clinical translation of FGF18-based protein drugs is hindered by their short half-life, low delivery efficiency and the need for repeated articular injections. This study proposes a CRISPR/Cas9-based approach to effectively activate the FGF18 gene of OA chondrocytes at the genome level in vivo, using chondrocyte-affinity peptide (CAP) incorporated hybrid exosomes (CAP/FGF18-hyEXO) loaded with an FGF18-targeted gene-editing tool. Furthermore, CAP/FGF18-hyEXO are encapsulated in methacrylic anhydride-modified hyaluronic (HAMA) hydrogel microspheres via microfluidics and photopolymerization to create an injectable microgel system (CAP/FGF18-hyEXO@HMs) with self-renewable hydration layers to provide persistent lubrication in response to frictional wear. Together, the injectable CAP/FGF18-hyEXO@HMs, combined with in vivo FGF18 gene editing and continuous lubrication, have demonstrated their capacity to synergistically promote cartilage regeneration, decrease inflammation, and prevent ECM degradation both in vitro and in vivo, holding great potential for clinical translation.

Comparison of face-based and voice-based first impressions in a Chinese sample.

People often form first impressions of others based on face and/or voice cues. This study aimed to compare the first impressions formed under these two cues. First, we compared free descriptions based on face and voice cues and found differences in the content and frequency of the personality words. We then compiled three wordlists used for face-based and voice-based first impression evaluations separately or simultaneously. Second, using these wordlists, we compared face-based and voice-based first impression ratings and found that both had significant intra-rater and inter-rater reliability. However, using the mean of the actors' self-rating and their acquaintance rating as the validity criterion, only the ratings of 'ingenuous' and 'mature' traits in the face-based first impression evaluation were significantly correlated with the validity criterion. Factor analysis revealed that face-based first impression had the dimensions of capability and approachability, while voice-based first impression had capability, approachability and reliability. The findings indicate that stable first impressions can be formed by either face or voice cues. However, the specific composition of impressions will vary between the cues. These results also provide a foundation for studying first impressions formed by an integrated perception of voice and face cues.

Ligand Mediation for Tunable and Oxide Suppressed Surface Gold-Decorated Liquid Metal Nanoparticles.

Gallium-based liquid metal systems hold vast potential in materials science. However, maximizing their possibilities is hindered by gallium's native oxide and interfacial functionalization. In this study, small-molecule ligands are adopted as surfactants to modify the surface of eutectic gallium indium (EGaIn) nanoparticles and suppress oxidation. Different p-aniline derivatives are explored. Next, the reduction of chloroanric acid (HAuCl4 ) onto these p-aniline ligand modified EGaIn nanoparticles is investigated to produce gold-decorated EGaIn nanosystems. It is found that by altering the concentrations of HAuCl4 or the p-aniline ligand, the formation of gold nanoparticles (AuNPs) on EGaIn can be manipulated. The reduction of interfacial oxidation and presence of AuNPs enhances electrical conductivity, plasmonic performance, wettability, stability, and photothermal performance of all the p-aniline derivative modified EGaIn. Of these, EGaIn nanoparticles covered with the ligand of p-aminobenzoic acid offer the most evenly distributed AuNPs decoration and perfect elimination of gallium oxides, resulting in the augmented electrical conductivity, and highest wettability suitable for patterning, enhanced aqueous stability, and favorable photothermal properties. The proof-of-concept application in photothermal therapy of cancer cells demonstrates significantly enhanced photothermal conversion performance along with good biocompatibility. Due to such unique characteristics, the developed gold-decorated EGaIn nanodroplets are expected to offer significant potential in precise medicine.

Attenuated memory impairment and neuroinflammation in Alzheimer's disease by aucubin via the inhibition of ERK-FOS axis.

Alzheimer's disease (AD) is a degenerative illness accompanied by cognitive and memory loss. In addition to the widely accepted, convincing amyloid cascade hypothesis, the activation of glial cells and neuroinflammation, especially the microglia-mediated neuroinflammation, has an essential role in the development and progression of AD. Therefore, the anti-inflammatory treatment is becoming a promising therapeutic strategy. Aucubin (Au) is a natural product derived from many plants with anti-inflammatory and antioxidant activities. Up to now, no research has been conducted to investigate the anti-inflammatory effects of Au and its neuroprotective quality on AD and the potential molecular mechanisms of its medical roles. In our study, the results of network pharmacology revealed the potential therapeutic effect of Au on AD. The results of studies in vivo showed that Au improved the behaviors, counteracted cognitive and memory deficits, and ameliorated AD-like pathological features of the mouse brain, e.g., the deposition of Aß plaques, neuronal damage, and inflammatory responses induced by glial cell overactivation, in APP/PS1 mice. The transcriptome sequencing further confirmed that the pathological symptoms of AD could be reversed by inhibiting the ERK/FOS axis to alleviate the inflammatory response. The in vitro experiments revealed that Au suppressed the BV2 cell activation, inhibited the phosphorylation of ERK1/2 and the expression of c-FOS, and reduced the LPS-induced inflammatory mediator production by BV2 cells and primary astrocytes. Our study suggested that Au exerted its neuroprotective effects by inhibiting the inflammatory responses, which could be a promising treatment of AD.

Green synthesis and anti-tumor efficacy via inducing pyroptosis of novel 1H-benzo[e]indole-2(3H)-one spirocyclic derivatives.

Pyroptosis induction is anticipated to be a new approach to developing anti-tumor medications. A novel class of spirocyclic compounds was designed by hybridization of 1H-Benzo[e]indole-2(3H)-one with 1,4-dihydroquinoline and synthesized through a new green "one-pot" synthesis method using 10 wt% SDS/H2O as a solvent to screen novel tumor cell pyroptosis inducers. The anti-tumor activity of all compounds in vitro was determined by the MTT method, and a fraction of the compounds showed good cell growth inhibitory activity. The quantitative structure-activity relationship models of the compounds were established by artificial intelligence random forest algorithm (R2 = 0.9656 and 0.9747). The ideal compound A9 could, in a concentration-dependent manner, prevent ovarian cancer cells from forming colonies, migrating, and invading. Furthermore, A9 could significantly induce pyroptosis and upregulate the expression of pyroptosis-related proteins GSDME-N, in addition to inducing apoptosis and mediating the expression of apoptosis-related proteins in ovarian cancer cells. A9 (5 mg/kg) significantly reduced tumor volume and weight of ovarian cancer in vivo, decreased caspase-3 expression in tumor tissue, and induced the production of GSDME-N. This study provides a green and efficient atom-economic synthesis method for 1H-Benzo[e]indole-2(3H)-one spirocyclic derivatives and a promising pyroptosis inducer with anti-tumor activity.

Omaveloxolone ameliorates cognitive dysfunction in APP/PS1 mice by stabilizing the STAT3 pathway.

AIMS: To determine the availability and the potential molecular mechanisms underlying the therapeutic effect of omaveloxolone (RTA408) on Alzheimer's Disease (AD). MATERIALS AND METHODS: This study employed network pharmacology to assess the feasibility of drug treatment of AD. To determine the cognitive status and emotional state of APPswe/PS1dE9 (APP/PS1) mice after the RTA408 treatment, three classical behavioral experiments (water maze, Y-maze, and open field test) were conducted. Immunofluorescence and immunohistochemical staining were utilized to evaluate hippocampal neuronal status and amyloid (Aß) deposition in mice. RNA-seq and transcription factor prediction analyses were performed to explore the potential molecular mechanisms regulating the therapeutic effects of RTA408. Molecular docking was employed to predict the direct drug targets. To validate these molecular mechanisms, quantitative reverse transcription PCR (qRT-PCR), Western blotting, and immunofluorescence analyses were performed in two instrumental cell lines, i.e., mouse hippocampal neuronal cells (HT22) and microglia (BV2). RESULTS: RTA408 was revealed with the capability to reduce Aß plaque deposition and to restore damaged neurons in the hippocampal region of APP/PS1 mice, ultimately leading to an improvement in cognitive function. This beneficial effect was achieved by balancing the STAT3 pathway. Specifically, RTA408 facilitated the activations of both STAT3/OXR1 and NRF2/ARE axes, thereby enhancing the compromised resistance in neurons to oxidative stress. RTA408 inhibited the NFκB/IL6/STAT3 pathway, effectively countering the neuroinflammation triggered by microglial activation. CONCLUSION: RTA408 is revealed with promising potential in the treatment of AD based on preclinical data.

The potential role of synovial cells in the progression and treatment of osteoarthritis.

Osteoarthritis (OA), the commonest arthritis, is characterized by the progressive destruction of cartilage, leading to disability. The Current early clinical treatment strategy for OA often centers on anti-inflammatory or analgesia medication, weight loss, improved muscular function and articular cartilage repair. Although these treatments can relieve symptoms, OA tends to be progressive, and most patients require arthroplasty at the terminal stages of OA. Recent studies have shown a close correlation between joint pain, inflammation, cartilage destruction and synovial cells. Consequently, understanding the potential mechanisms associated with the action of synovial cells in OA could be beneficial for the clinical management of OA. Therefore, this review comprehensively describes the biological functions of synovial cells, the synovium, together with the pathological changes of synovial cells in OA, and the interaction between the cartilage and synovium, which is lacking in the present literature. Additionally, therapeutic approaches based on synovial cells for OA treatment are further discussed from a clinical perspective, highlighting a new direction in the treatment of OA.

Atherosclerotic plaque vulnerability quantification system for clinical and biological interpretability.

Acute myocardial infarction dominates coronary artery disease mortality. Identifying bio-signatures for plaque destabilization and rupture is important for preventing the transition from coronary stability to instability and the occurrence of thrombosis events. This computational systems biology study enrolled 2,235 samples from 22 independent bulks cohorts and 14 samples from two single-cell cohorts. A machine-learning integrative program containing nine learners was developed to generate a warning classifier linked to atherosclerotic plaque vulnerability signature (APVS). The classifier displays the reliable performance and robustness for distinguishing ST-elevation myocardial infarction from chronic coronary syndrome at presentation, and revealed higher accuracy to 33 pathogenic biomarkers. We also developed an APVS-based quantification system (APVSLevel) for comprehensively quantifying atherosclerotic plaque vulnerability, empowering early-warning capabilities, and accurate assessment of atherosclerosis severity. It unraveled the multidimensional dysregulated mechanisms at high resolution. This study provides a potential tool for macro-level differential diagnosis and evaluation of subtle genetic pathological changes in atherosclerosis.

Optimization of exosome-based cell-free strategies to enhance endogenous cell functions in tissue regeneration.

Exosomes, nanoscale extracellular vesicles, play a crucial role in intercellular communication, owing to their biologically active cargoes such as RNAs and proteins. In recent years, they have emerged as a promising tool in the field of tissue regeneration, with the potential to initiate a new trend in cell-free therapy. However, it's worth noting that not all types of exosomes derived from cells are appropriate for tissue repair. Thus, selecting suitable cell sources is critical to ensure their efficacy in specific tissue regeneration processes. Current therapeutic applications of exosomes also encounter several limitations, including low-specific content for targeted diseases, non-tissue-specific targeting, and short retention time due to rapid clearance in vivo. Consequently, this review paper focuses on exosomes from diverse cell sources with functions specific to tissue regeneration. It also highlights the latest engineering strategies developed to overcome the functional limitations of natural exosomes. These strategies encompass the loading of specific therapeutic contents into exosomes, the endowment of tissue-specific targeting capability on the exosome surface, and the incorporation of biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. Collectively, these innovative approaches aim to synergistically enhance the therapeutic effects of natural exosomes, optimizing exosome-based cell-free strategies to boost endogenous cell functions in tissue regeneration. STATEMENT OF SIGNIFICANCE: Exosome-based cell-free therapy has recently emerged as a promising tool for tissue regeneration. This review highlights the characteristics and functions of exosomes from different sources that can facilitate tissue repair and their contributions to the regeneration process. To address the functional limitations of natural exosomes in therapeutic applications, this review provides an in-depth understanding of the latest engineering strategies. These strategies include optimizing exosomal contents, endowing tissue-specific targeting capability on the exosome surface, and incorporating biomaterials to extend the in vivo retention time of exosomes in a controlled-release manner. This review aims to explore and discuss innovative approaches that can synergistically improve endogenous cell functions in advanced exosome-based cell-free therapies for a broad range of tissue regeneration.

Cell-Free Osteoarthritis Treatment with Sustained-Release of Chondrocyte-Targeting Exosomes from Umbilical Cord-Derived Mesenchymal Stem Cells to Rejuvenate Aging Chondrocytes.

As chondrocytes from osteoarthritic cartilage usually exhibit aging and senescent characteristics, targeting aging chondrocytes could be a potential therapeutic strategy. In this study, exosomes derived from umbilical cord-derived mesenchymal stem cells (UCMSC-EXOs) combined with the chondrocyte-targeting capacity and controlled-release system were proposed for osteoarthritis (OA) treatment via rejuvenating aging chondrocytes. The essential functional miRNAs within UCMSC-EXOs were investigated, with the p53 signaling pathway identified as the key factor. To improve the therapeutic efficiency and retention time of UCMSC-EXOs in vivo, the exosomes (EXOs) were engineered on membranes with a designed chondrocyte-targeting polymers, and encapsulated within thiolated hyaluronic acid microgels to form a "two-phase" releasing system, which synergistically facilitated the repair of OA cartilage in a rat model. Together, this study highlighted the rejuvenating effects of UCMSC-EXOs on OA chondrocytes and the potential to combine with chondrocyte-targeting and sustained-release strategies toward a future cell-free OA treatment.