Myocardial reperfusion injury exacerbation due to ALDH2 deficiency is mediated by neutrophil extracellular traps and prevented by leukotriene C4 inhibition.

BACKGROUND AND AIMS: The Glu504Lys polymorphism in the aldehyde dehydrogenase 2 (ALDH2) gene is closely associated with myocardial ischaemia/reperfusion injury (I/RI). The effects of ALDH2 on neutrophil extracellular trap (NET) formation (i.e. NETosis) during I/RI remain unknown. This study aimed to investigate the role of ALDH2 in NETosis in the pathogenesis of myocardial I/RI. METHODS: The mouse model of myocardial I/RI was constructed on wild-type, ALDH2 knockout, peptidylarginine deiminase 4 (Pad4) knockout, and ALDH2/PAD4 double knockout mice. Overall, 308 ST-elevation myocardial infarction patients after primary percutaneous coronary intervention were enrolled in the study. RESULTS: Enhanced NETosis was observed in human neutrophils carrying the ALDH2 genetic mutation and ischaemic myocardium of ALDH2 knockout mice compared with controls. PAD4 knockout or treatment with NETosis-targeting drugs (GSK484, DNase1) substantially attenuated the extent of myocardial damage, particularly in ALDH2 knockout. Mechanistically, ALDH2 deficiency increased damage-associated molecular pattern release and susceptibility to NET-induced damage during myocardial I/RI. ALDH2 deficiency induced NOX2-dependent NETosis via upregulating the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/leukotriene C4 (LTC4) pathway. The Food and Drug Administration-approved LTC4 receptor antagonist pranlukast ameliorated I/RI by inhibiting NETosis in both wild-type and ALDH2 knockout mice. Serum myeloperoxidase-DNA complex and LTC4 levels exhibited the predictive effect on adverse left ventricular remodelling at 6 months after primary percutaneous coronary intervention in ST-elevation myocardial infarction patients. CONCLUSIONS: ALDH2 deficiency exacerbates myocardial I/RI by promoting NETosis via the endoplasmic reticulum stress/microsomal glutathione S-transferase 2/LTC4/NOX2 pathway. This study hints at the role of NETosis in the pathogenesis of myocardial I/RI, and pranlukast might be a potential therapeutic option for attenuating I/RI, particularly in individuals with the ALDH2 mutation.

Defining the relationship of salivary gland malignancies to novel cell subpopulations in human salivary glands using single nucleus RNA-sequencing.

Salivary glands have essential roles in maintaining oral health, mastication, taste and speech, by secreting saliva. Salivary glands are composed of several types of cells, and each cell type is predicted to be involved in the carcinogenesis of different types of cancers including adenoid cystic carcinoma (ACC), acinic cell carcinoma (AciCC), salivary duct carcinoma (SDC), myoepithelial carcinoma (MECA) and other histology. In our study, we performed single nucleus RNA-seq on three human salivary gland samples to clarify the gene expression profile of each complex cellular component of the salivary glands and related these expression patterns to expression found in salivary gland cancers (SGC) to infer cell of origin. By single nucleus RNA-seq, salivary gland cells were stratified into four clusters: acinar cells, ductal cells 1, ductal cells 2 and myoepithelial cells/stromal cells. The localization of each cell group was verified by IHC of each cluster marker gene, and one group of ductal cells was found to represent intercalated ductal cells labeled with HES1. Furthermore, in comparison with SGC RNA-seq data, acinar cell markers were upregulated in AciCC, but downregulated in ACC and ductal cell markers were upregulated in SDC but downregulated in MECA, suggesting that markers of origin are highly expressed in some SGC. Cell type expressions in specific SGC histology are similar to those found in normal salivary gland populations, indicating a potential etiologic relationship.

Ultrafast and Highly Specific Detection of One-Base Mutated Cell-Free DNA at a Very Low Abundance.

Liquid biopsy as well as genotyping plays important roles in guiding the use of tumor-targeted drugs and monitoring the generation of drug resistance. However, current methods, such as next-generation sequencing (NGS) and pyrosequencing, require long analysis time and complicated steps. To achieve ultrafast and highly specific detection of cell-free DNA (cfDNA) from blood, we improved our recently developed FEN1-aided RPA (FARPA), which combined flap endonuclease 1 (FEN1)-catalyzed invasive reactions with recombinase polymerase amplification (RPA) by inactivating the RPA enzymes before invasive reactions, designing short RPA primers, and changing invasive reaction conditions. Using the L858R and T790M mutations as examples, FARPA was sensitive to detect 5 copies of targeted mutants, specific to sense the mutants with an abundance as low as 0.01% from blood, and ultrafast to get results within 40 min. The method was readily expended to genotyping, and 15 min was enough to report the allele species directly from oral swab samples by coupling quick DNA extraction reagents. Validation was carried out by detecting clinical samples, including 20 cfDNA from patients with non-small cell lung cancer (NSCLC) for liquid biopsy and 43 human genomic DNA (gDNA) purified from blood (33) or lysed from oral swabs (10) for genotyping, giving 100% agreement with NGS and pyrosequencing, respectively. Furthermore, a portable battery-driven device with dual-channel fluorescence detection was successfully constructed to facilitate point-of-care testing (POCT) of liquid biopsy and genotyping, providing doctors with a potential tool to achieve genotyping- or mutant-guided personalized medicine at emergency or source-limited regions.

Altitudinal patterns of alpine soil ammonia-oxidizing community structure and potential nitrification rate.

Nitrogen availability limits the net primary productivity in alpine meadows on the Qinghai-Tibetan Plateau, which is regulated by ammonia-oxidizing microorganisms. However, little is known about the elevational patterns of soil ammonia oxidizers in alpine meadows. Here, we investigated the potential nitrification rate (PNR), abundance, and community diversity of soil ammonia-oxidizing microorganisms along the altitudinal gradient between 3,200 and 4,200 m in Qinghai-Tibetan alpine meadows. We found that both PNR and amoA gene abundance declined from 3,400 to 4,200 m but lowered at 3,200 m, possibly due to intense substrate competition and biological nitrification inhibition from grasses. The primary contributors to soil nitrification were ammonia-oxidizing archaea (AOA), and their proportionate share of soil nitrification increased with altitude in comparison to ammonia-oxidizing bacteria (AOB). The alpha diversity of AOA increased by higher temperature and plant richness at low elevations, while decreased by higher moisture and low legume biomass at middle elevations. In contrast, the alpha diversity of AOB increased along elevation. The elevational patterns of AOA and AOB communities were primarily driven by temperature, soil moisture, and vegetation. These findings suggest that elevation-induced climate changes, such as shifts in temperature and water conditions, could potentially alter the soil nitrification process in alpine meadows through changes in vegetation and soil properties, which provide new insights into how soil ammonia oxidizers respond to climate change in alpine meadows.IMPORTANCEThe importance of this study is revealing that elevational patterns and nitrification contributions of ammonia-oxidizing archaea (AOA) and ammonia-oxidizing bacteria (AOB) communities were primarily driven by temperature, soil moisture, and vegetation. Compared to AOB, the relative contribution of AOA to soil nitrification increased at higher elevations. The research highlights the potential impact of elevation-induced climate change on nitrification processes in alpine meadows, mediated by alterations in vegetation and soil properties. By providing new insights into how ammonia oxidizers respond to climate change, this study contributes valuable knowledge to the field of microbial ecology and helps predict ecological responses to environmental changes in alpine meadows.

Mesencephalic astrocyte-derived neurotrophic factor inhibits cervical cancer progression via regulating macrophage phenotype.

BACKGROUND: Cervical cancer is a common gynecologic malignant tumor, but the critical factors affecting cervical cancer progression are still not well demonstrated. Mesencephalic astrocyte-derived neurotrophic factor (MANF) has been widely recognized as an anti-inflammatory factor to regulate macrophage polarization. In this study, the effect and mechanism of MANF on cervical cancer were preliminarily explored. METHODS AND RESULTS: Kaplan-Meier curve was used to show the overall survival time of the involved cervical cancer patients with high and low MANF expression in cervical cancer tissues. MANF was highly expressed in peritumoral tissues of cervical carcinoma by using immunohistochemistry and western blot. MANF mRNA level was detected by using qRT-PCR. Dual-labeled immunofluorescence showed MANF was mainly expressed in macrophages of cervical peritumoral tissues. Moreover, MANF-silenced macrophages promoted HeLa and SiHa cells survival, migration, invasion and EMT via NF-κB signaling activation. The results of tumor formation in nude mice indicated MANF-silenced macrophages promoted cervical tumor formation in vivo. CONCLUSION: Our study reveals an inhibitory role of MANF in cervical cancer progression, indicating MANF as a new and valuable therapeutic target for cervical cancer treatment.

Water hyacinth derived hierarchical porous biochar absorbent: Ideal peroxydisulfate activator for efficient phenol degradation via an electron-transfer pathway.

In this paper, a facile hydrothermal pretreatment and molten salt activation route was presented for preparing a self-doped porous biochar (HMBC) from a nitrogenous biomass precursor of water hyacinth. With an ultrahigh specific surface area (2240 m2 g-1), well-developed hierarchical porous structure, created internal structural defects and doped surface functionalities, HMBC exhibited an excellent adsorption performance and catalytic activity for phenol removal via peroxydisulfate (PDS) activation. Specifically, the porous structure promoted the adsorption of PDS on HMBC, forming a highly active HMBC/PDS* complex and thereby increasing the oxidation potential of the system. Meanwhile, the carbon defective structure, graphitic N and CO groups enhanced the electron transfer process, favoring the HMBC/PDS system to catalyze phenol oxidation via an electron transfer dominated pathway. Thus, the system degraded phenol effectively with an ultralow activation energy of 4.9 kJ mol-1 and a remarkable oxidant utilization efficiency of 8.2 mol mol-oxidant-1 h-1 g-1. More importantly, the system exhibited excellent resistance to water quality and good adaptability for decontaminating different organic pollutants with satisfactory mineralization efficiency. This study offers valuable insights into the rational designing of a low-cost biochar catalyst for efficient PDS activation towards organic wastewater remediation.

Bimodal DNA self-origami material with nucleic acid function enhancement.

BACKGROUND: The design of DNA materials with specific nanostructures for biomedical tissue engineering applications remains a challenge. High-dimensional DNA nanomaterials are difficult to prepare and are unstable; moreover, their synthesis relies on heavy metal ions. Herein, we developed a bimodal DNA self-origami material with good biocompatibility and differing functions using a simple synthesis method. We simulated and characterized this material using a combination of oxDNA, freeze-fracture electron microscopy, and atomic force microscopy. Subsequently, we optimized the synthesis procedure to fix the morphology of this material. RESULTS: Using molecular dynamics simulation, we found that the bimodal DNA self-origami material exhibited properties of spontaneous stretching and curling and could be fixed in a single morphology via synthesis control. The application of different functional nucleic acids enabled the achievement of various biological functions, and the performance of functional nucleic acids was significantly enhanced in the material. Consequently, leveraging the various functional nucleic acids enhanced by this material will facilitate the attainment of diverse biological functions. CONCLUSION: The developed design can comprehensively reveal the morphology and dynamics of DNA materials. We thus report a novel strategy for the construction of high-dimensional DNA materials and the application of functional nucleic acid-enhancing materials.

Functional SNPs in SYISL promoter significantly affect muscle fiber density and muscle traits in pigs.

Our previous studies showed that SYISL is a negative regulator of muscle growth and regeneration in mice, pigs and humans. SYISL knockout resulted in an increase in the density of muscle fibers and muscle growth. However, it is unclear whether there are natural mutations in pig SYNPO2 intron sense-overlapping lncRNA (pSYISL) that affect the expression of pSYISL and muscle growth traits. In this study, three SNPs in exons and six SNPs within the promoter of pSYISL were identified. Association analysis showed that the two SNPs in exons are significantly associated with loin muscle area (p < 0.05); the six SNPs in the promoter that show complete linkage are significantly associated with live backfat thickness and live loin muscle area in American Large White pigs. Bioinformatics and luciferase reporter assays as well as in vitro binding experiments indicated that the mutation of SNP rs702045770 (g.539G>A) leads to the loss of YY1 binding to the promoter, thus affecting the expression level of pSYISL, and we found that Jiangshan Black pigs with genotype GG have a higher expression level of pSYISL than genotype AA individuals, but the muscle fiber density was significantly lower than in genotype AA individuals. Furthermore, the association analysis showed that the carcass backfat thickness of genotype GG of SNP rs702045770 was significantly higher than that of other genotypes in (Pietrain × Duroc) × (Landrace × Yorkshire) crossbred pigs (p < 0.05). The glycolytic potential of genotype GG was significantly higher than that of other genotypes (p < 0.05). These results provide novel insight into the identification of functional SNPs in non-coding genomic regions.

Effects of high-flow nasal cannula oxygen therapy in bronchiectasis and hypercapnia: a retrospective observational study.

BACKGROUND: The effectiveness of high-flow nasal cannula (HFNC) therapy in patients with bronchiectasis experiencing hypercapnia remains unclear. Our aim was to retrospectively analyze the short-term outcomes of HFNC therapy in such patients, and to further explore the predictors of HFNC treatment failure in this particular patient population. METHODS: A retrospective review was conducted on patients with bronchiectasis who received HFNC (n = 70) for hypercapnia (arterial partial pressure of carbon dioxide, PaCO2 ≥ 45 mmHg) between September 2019 and September 2023. RESULTS: In the study population, 30% of patients presented with acidemia (arterial pH < 7.35) at baseline. Within 24 h of HFNC treatment, there was a significant reduction in PaCO2 levels by a mean of 4.0 ± 12.7 mmHg (95% CI -7.0 to -1.0 mmHg). Concurrently, arterial pH showed a statistically significant increase with a mean change of 0.03 ± 0.06 (95% CI 0.01 to 0.04). The overall hospital mortality rate in our study was 17.5%. The median length of hospital stay was 11.0 days (interquartile range [IQR] 8.0 to 16.0 days). Sub-analysis revealed no statistically significant differences in hospital mortality (19.0% vs. 20.4%, p = 0.896), length of hospital stay (median 14.0 days [IQR 9.0 to 18.0 days] vs. 10.0 days [IQR 7.0 to 16.0 days], p = 0.117) and duration of HFNC application (median 5.0 days [IQR 2.0 to 8.5 days] vs. 6.0 days [IQR 4.9 to 9.5 days], p = 0.076) between the acidemia group and the non-acidemia group (arterial pH ≥ 7.35). However, more patients in the non-acidemia group had do-not-intubate orders. The overall treatment failure rate for HFNC was 28.6%. Logistic regression analysis identified the APACHE II score (OR 1.24 per point) as the independent predictor of HFNC failure. CONCLUSIONS: In patients with bronchiectasis and hypercapnia, HFNC as an initial respiratory support can effectively reduce PaCO2 level within 24 h of treatment. A high APACHE II score has emerged as a prognostic indicator for HFNC treatment failure. These observations highlight randomized controlled trials to meticulously evaluate the efficacy of HFNC in this specific population.

Implication of m6A Methylation Regulators in the Immune Microenvironment of Bronchopulmonary Dysplasia.

N6-methyladenosine (m6A) regulates gene expression and governs many important biological processes. However, the function of m6A in the development of bronchopulmonary dysplasia (BPD) remains poorly characterized. Thus, the purpose of this investigation was to evaluate the effects of m6A RNA methylation regulators on the development of BPD. BPD-related transcriptome data were downloaded from the GEO database. Differentially expressed m6A methylation regulators between BPD and control group were identified. Consensus clustering was conducted for the classification of BPD and association between clusters and BPD phenotypes were explored. Analysis of differentially expressed genes (DEGs) and immune-related DEGs was performed. The GSEA, GO and KEGG analyses were used to interpret the functional enrichments. The composition of immune cell subtypes in BPD subsets was predicted by CIBERSORT analysis. Compared with the control group, expression of most m6A regulators showed significant alteration, especially for IGF2BP1/2/3. BPD was classified into 2 subsets, and cluster 1 was correlated with severe BPD. Furthermore, the results of functional enrichment analyses showed a disturbed immune-related signaling pathway. Based on CIBERSORT analysis, we found that the proportion of immune cell subsets changed between cluster 1 and cluster 2. Our study revealed the implication of m6A methylation regulators in the development of BPD, which might provide a novel insight for the diagnosis and treatment of BPD.

Targeting Proteins in Nucleus through Dual-Regulatory Pathways Acting in Cytoplasm.

Nuclear proteins have been regarded as attractive targets for exploiting therapeutic agents. However, those agents cannot efficiently pass through nuclear pores and it is also difficult to overcome the crowded nuclear environment to react with proteins. Herein, we propose a novel strategy acting in the cytoplasm to regulate nuclear proteins based on their signaling pathways, instead of directly entering into nuclei. A multifunctional complex PKK-TTP/hs carries human telomerase reverse transcriptase (hTERT) small interfering RNA (defined as hs) for gene silencing in the cytoplasm, which reduced the import of nuclear protein. At the same time, it could generate reactive oxygen species (ROS) under light irradiation, which raised the export of nuclear proteins by promoting proteins translocation. Through this dual-regulatory pathway, we successfully reduced nuclear protein (hTERT proteins) in vivo (42.3%). This work bypasses the challenge of directly entering into the nucleus and provides an effective strategy for regulating nuclear proteins.

Cell Membrane as A Promising Therapeutic Target: From Materials Design to Biomedical Applications.

The cell membrane is a crucial component of cells, protecting their integrity and stability while facilitating signal transduction and information exchange. Therefore, disrupting its structure or impairing its functions can potentially cause irreversible cell damage. Presently, the tumor cell membrane is recognized as a promising therapeutic target for various treatment methods. Given the extensive research focused on cell membranes, it is both necessary and timely to discuss these developments, from materials design to specific biomedical applications. This review covers treatments based on functional materials targeting the cell membrane, ranging from well-known membrane-anchoring photodynamic therapy to recent lysosome-targeting chimaeras for protein degradation. The diverse therapeutic mechanisms are introduced in the following sections: membrane-anchoring phototherapy, self-assembly on the membrane, in situ biosynthesis on the membrane, and degradation of cell membrane proteins by chimeras. In each section, we outline the conceptual design or general structure derived from numerous studies, emphasizing representative examples to understand advancements and draw inspiration. Finally, we discuss some challenges and future directions in membrane-targeted therapy from our perspective. This review aims to engage multidisciplinary readers and encourage researchers in related fields to advance the fundamental theories and practical applications of membrane-targeting therapeutic agents.

Nanofibers in Organelles: From Structure Design to Biomedical Applications.

Nanofibers are one of the most important morphologies of molecular self-assemblies, the formation of which relies on the diverse intermolecular interactions of fibrous-forming units. In the past decade, rapid advances have been made in the biomedical application of nanofibers, such as bioimaging and tumor treatment. An important topic to be focused on is not only the nanofiber formation mechanism but also where it forms, because different destinations could have different influences on cells and its formation could be triggered by unique stimuli in organelles. It is therefore necessary and timely to summarize the nanofibers assembled in organelles. This minireview discusses the formation mechanism, triggering strategies, and biomedical applications of nanofibers, which may facilitate the rational design of nanofibers, improve our understanding of the relationship between nanofiber properties and organelle characteristics, allow a comprehensive recognition of organelles affected by materials, and enhance the therapeutic efficiency of nanofibers.

A Fluorous Peptide Amphiphile with Potent Antimicrobial Activity for the Treatment of MRSA-induced Sepsis and Chronic Wound Infection.

The rising prevalence of global antibiotic resistance evokes the urgent need for novel antimicrobial candidates. Cationic lipopeptides have attracted much attention due to their strong antimicrobial activity, broad-spectrum and low resistance tendency. Herein, a library of fluoro-lipopeptide amphiphiles was synthesized by tagging a series of cationic oligopeptides with a fluoroalkyl tail via a disulfide spacer. Among the lipopeptide candidates, R6F bearing six arginine moieties and a fluorous tag shows the highest antibacterial activity, and it exhibits an interesting fluorine effect as compared to the non-fluorinated lipopeptides. The high antibacterial activity of R6F is attributed to its excellent bacterial membrane permeability, which further disrupts the respiratory chain redox stress and cell wall biosynthesis of the bacteria. By co-assembling with lipid nanoparticles, R6F showed high therapeutic efficacy and minimal adverse effects in the treatment of MRSA-induced sepsis and chronic wound infection. This work provides a novel strategy to design highly potent antibacterial peptide amphiphiles for the treatment of drug-resistant bacterial infections.

A Universal and Programmable Platform based on Fluorescent Peptide-Conjugated Probes for Detection of Proteins in Organelles of Living Cells.

Realizing protein analysis in organelles of living cells is of great significance for developing diagnostic and therapeutic methods of diseases. Fluorescent-labeled antibodies with well imaging performance and high affinity are classical biochemical tools for protein analysis, while due to the inability to effectively enter into cells, not to mention organelles and the uncontrollable reaction sites that might cause antibodies inactivation when chemically modification, they are hard to apply to living cells. Inspired by the structure of fluorescent-labeled antibodies, we designed as a universal detection platform that was based on the peptide-conjugated probes (PCPs) and consisted of three parts: a) a rotor type fluorescent molecular scaffold for conjugation and signal output; b) the cell penetration protein recognition unit; c) the subcellular organelle targeting unit. In living cells, PCPs could firstly localize at organelles and then proceed protein specific recognition, thus jointly leading to the restriction of twisted intramolecular charge transfer and activation of fluorescence signal. As a proof-of-concept, six different proteins in three typical intracellular organelles could be detected by our platform through simply replacing the recognition sequence of proteins and matching organelle targeting units. The position and intensity of fluorescence signals demonstrated specificity of PCPs and universality of the platform.

Photo-Controlled Calcium Overload from Endogenous Sources for Tumor Therapy.

Designing reactive calcium-based nanogenerators to produce excess calcium ions (Ca2+ ) in tumor cells is an attractive tumor treatment method. However, nanogenerators that introduce exogenous Ca2+ are either overactive incapable of on-demand release, or excessively inert incapable of an overload of calcium rapidly. Herein, inspired by inherently diverse Ca2+ -regulating channels, a photo-controlled Ca2+ nanomodulator that fully utilizes endogenous Ca2+ from dual sources was designed to achieve Ca2+ overload in tumor cells. Specifically, mesoporous silica nanoparticles were used to co-load bifunctional indocyanine green as a photodynamic/photothermal agent and a thermal-sensitive nitric oxide (NO) donor (BNN-6). Thereafter, they were coated with hyaluronic acid, which served as a tumor cell-targeting unit and a gatekeeper. Under near-infrared light irradiation, the Ca2+ nanomodulator can generate reactive oxygen species that stimulate the transient receptor potential ankyrin subtype 1 channel to realize Ca2+ influx from extracellular environments. Simultaneously, the converted heat can induce BNN-6 decomposition to generate NO, which would open the ryanodine receptor channel in the endoplasmic reticulum and allow stored Ca2+ to leak. Both in vitro and in vivo experiments demonstrated that the combination of photo-controlled Ca2+ influx and release could enable Ca2+ overload in the cytoplasm and efficiently inhibit tumor growth.

Regulating the Membrane Affinity of Multi-module Probes to Address the Trade-off between Anchoring and Internalization.

Cell membrane transport is the first and crucial step for bioprobes to realize the diagnosis, imaging, and therapy in cells. However, during this transport, there is a trade-off between anchoring and internalization steps, which will seriously affect the membrane transport efficiency. In the past, because the interaction between probes and cell membrane is constant, this challenge is hard to solve. Here, we proposed a strategy to regulate the membrane affinity of multi-module probes that enabled probe to have strong affinity during cell membrane anchoring and weak affinity during internalization. Specifically, a multi-module probe defined as LK-M-NA was constructed, which consisted of three main parts, membrane-anchoring α-helix peptide (LK), anchoring regulator (M), and therapeutic module (NA). With the α-helix module, LK-M-NA was able to rapidly anchor on the cell membrane and the binding energy was -1450.90 kcal/mol. However, after pericellular cleavage by the highly active matrix metalloproteinase-2 , LK could be removed due to the breakage of M and the binding energy reduced to -869.95 kcal/mol. Thus, the internalization restriction caused by high affinity was relieved. Owing to the alterable affinity, the membrane transport efficiency of LK-M-NA increased to 14.58%, well addressing the trade-off problem.

Peptide-Conjugated Probe Inducing Mitochondrial Dysfunction and Self-Reporting Cell Apoptosis by Aggregated Proteins.

Inducing and monitoring cell apoptosis in a real-time manner are crucial for evaluating the therapeutic effect of drugs and avoiding excessive treatment. Although promising advancements have been made to monitor cell apoptosis by assessing cell membrane integrity, the chronic compromise of cellular fitness caused by imbalance proteostasis is not visible and hard to be detected. As an indicator for cell apoptosis, imaging of aggregated proteins provides a new direction. Herein, we design a peptide-conjugated probe (QRKN) that can induce mitochondrial dysfunction for self-reporting cell apoptosis by imaging aggregated proteins. Specifically, QRKN can be cleaved into the α-helix-forming part (QRK) and azide-modified small-molecule part (N) by overexpressed cathepsin B (CB) in tumor cells. The QRK part can destroy the mitochondrial membrane and promote cytochrome c (Cyt c) efflux and caspase 3 expression. The other N part can inhibit the activity of mitochondrial complex IV (Mito-IV) and decrease the expression level of adenosine triphosphate (ATP). Two signaling pathways cooperatively induce mitochondrial dysfunction, resulting in protein aggregation and cell apoptosis ultimately. Meanwhile, the cell apoptosis process can be monitored based on QRKN, which is highly sensitive to the aggregated protein-triggered viscosity change. The self-reporting probe can monitor therapeutic responses and provide valuable diagnosis information.

Cancer-Associated Fibroblast Mimetic AIE Probe for Precision Imaging-Guided Full-Cycle Management of Ovarian Cancer Surgery.

Fluorescence imaging can improve surgical accuracy in ovarian cancer, but a high signal-to-noise ratio is crucial for tiny metastatic cancers. Meanwhile, intraoperative fluorescent surgical navigation modalities alone are still insufficient to completely remove ovarian cancer lesions, and the recurrence rate remains high. Here, we constructed a cancer-associated fibroblasts (CAFs)-mimetic aggregation-induced emission (AIE) probe to enable full-cycle management of surgery that eliminates recurrence. AIE molecules (P3-PPh3) were packed in hollow mesoporous silica nanoparticles (HMSNs) to form HMSN-probe and then coated with a CAFs membrane to prepare CAF-probe. First, due to the negative potential of the CAF-probe, the circulation time in vivo is elevated, which facilitates passive tumor targeting. Second, the CAF-probe avoids its clearance by the immune system and improves the bioavailability. Finally, the fibronectin on the CAF-probe specifically binds to integrin α-5 (ITGA5), which is highly expressed in ovarian cancer cells, enabling fluorescence imaging with a contrast of up to 8.6. CAF-probe-based fluorescence imaging is used to evaluate the size and location of ovarian cancer before surgery (preoperative evaluation), to guide tumor removal during surgery (intraoperative navigation), and to monitor tumor recurrence after surgery (postoperative monitoring), ultimately significantly improving the efficiency of surgery and completely eliminating tumor recurrence. In conclusion, we constructed a CAFs mimetic AIE probe and established a full-cycle surgical management model based on its precise imaging properties, which significantly reduced the recurrence of ovarian cancer.