Microfluidic synthesis of hemin@ZIF-8 nanozyme with applications in cellular reactive oxygen species detection and anticancer drug screening.

Zeolitic imidazolate framework-8 (ZIF-8) encapsulating enzymatically active biomolecules has emerged as a novel biocompatible nanozyme and offers significant implications for bioanalysis of various biomarkers towards early diagnosis of severe diseases such as cancers. However, the rapid, continuous and scalable synthesis of these nanozymes still remains challenging. In this work, we proposed a novel microfluidic approach for rapid and continuous synthesis of hemin@ZIF-8 nanozyme. By employing a distinctive combination of zigzag-shaped channel and spiral channel with sudden expansion structures, we have enhanced the mixing efficiency within the chip and achieved effective encapsulation of hemin in ZIF-8. The resulting hemin@ZIF-8 nanoparticles exhibit peroxidase-like activity and are capable of detecting free H2O2 with a limit of detection (LOD) as low as 45 nM, as well as H2O2 secreted by viable cells with a detection threshold of approximately 10 cells per mL. By leveraging this method, we achieved successful detection of cancer cells and effective screening of anticancer drugs that induce oxidative stress injury in cancer cells. This innovative microfluidic strategy offers a new avenue for synthesizing functional nanocomposites to facilitate the development of next-generation diagnostic tools for early disease detection and personalized medicine.

The association of CSF biomarkers and cognitive decline with choroid plexus volume in early Parkinson's disease.

OBJECTIVE: This study aims to determine the link between choroid plexus (CP) volume and cognitive decline in patients with early-stage Parkinson's disease (PD) and to test whether pathological proteins in the cerebrospinal fluid (CSF) are involved in the modulation of any detrimental effects from CP volume. METHODS: Data on 95 early-stage PD patients with 5 years of follow-up were collected from the Parkinson's Progression Marker Initiative cohort. The patients were separated into three groups based on tertiles of baseline CP volume. We then used a linear mixed model for longitudinal analysis and conducted path analysis to investigate mediating effects. RESULTS: At baseline, the patients in both the upper and middle tertile group were older and had lower concentrations of CSF Aß1-42 than those in the lowest tertile group. Longitudinal analysis showed that the upper tertile group suffered from a more rapid cognitive decline in the Symbol Digit Modalities test, Hopkins Verbal Learning Test (HVLT)-retention, and HVLT delayed recalled score. Furthermore, path analysis showed that the pathological effects of CP volume on the 5-year decline in memory might be partly mediated by the CSF Aß1-42/αsyn ratio. CONCLUSION: CP enlargement could be an independent risk factor for decreased cognition in patients with early-stage PD, and this risk may be mediated by CSF pathological proteins.

TREM2 Deficiency Aggravates NLRP3 Inflammasome Activation and Pyroptosis in MPTP-Induced Parkinson's Disease Mice and LPS-Induced BV2 Cells.

Microglia-mediated neuroinflammation plays a crucial role in the pathogenesis of Parkinson's disease (PD). Triggering receptor expressed on myeloid cells 2 (TREM2) confers strong neuroprotective effects in PD by regulating the phenotype of microglia. Recent studies suggest that TREM2 regulates high glucose-induced microglial inflammation through the NLRP3 signaling pathway. This study aimed to investigate the effect of TREM2 on NLRP3 inflammasome activation and neuroinflammation in PD. Mice were injected with AAV-TREM2-shRNA into both sides of the substantia nigra using a stereotactic injection method, followed by intraperitoneal injection of MPTP to establish chronic PD mouse model. Behavioral assessments including the pole test and rotarod test were conducted to evaluate the effects of TREM2 deficiency on MPTP-induced motor dysfunction. Immunohistochemistry of TREM2 and tyrosine hydroxylase (TH), immunohistochemistry and immunofluorescence Iba1, Western blot of NLRP3 inflammasome and its downstream inflammatory factors IL-1ß and IL-18, and the key pyroptosis factors GSDMD and GSDMD-N were performed to explore the effect of TREM2 on NLRP3 inflammasome and neuroinflammation. In an in vitro experiment, lentivirus was used to interfere with the expression of TREM2 in BV2 microglia, and then lipopolysaccharide (LPS) and adenopterin nucleoside triphosphate (ATP) were used to stimulate inflammation to construct a cellular inflammation model. The expression differences of NLRP3 inflammasome and its components were detected by qPCR and Western blot. In vivo, TREM2 knockdown aggravated the loss of dopaminergic neuron and the decline of motor function. After TREM2 knockdown, the number of activated microglia was significantly increased, and the expression of cleaved caspase-1, NLRP3 inflammasome, IL-1ß, GSDMD, and GSDMD-N was increased. In vitro, TREM2 knockdown aggravated the inflammatory response of BV2 cells stimulated by LPS and promoted the activation of NLRP3 inflammasome through the NF-κB pathway. In addition, TREM2 knockdown also promoted the expression of TLR4/MyD88, an upstream factor of the NF-κB pathway. Our vivo and vitro data showed that TREM2 knockdown promoted NLRP3 inflammasome activation and downstream inflammatory response, promoted pyroptosis, and aggravated dopaminergic neuron loss. TREM2 acts as an anti-inflammatory in PD through the TLR4/MyD88/NF-κB pathway, which extends previous findings and supports the notion that TREM2 ameliorates neuroinflammation in PD.

A Gene-Editable Palladium-Based Bioorthogonal Nanoplatform Facilitates Macrophage Phagocytosis for Tumor Therapy.

Macrophage phagocytosis of tumor cells has emerged as an attractive strategy for tumor therapy. Nevertheless, immunosuppressive M2 macrophages in the tumor microenvironment and the high expression of anti-phagocytic signals from tumor cells impede therapeutic efficacy. To address these issues and improve the management of malignant tumors, in this study we developed a gene-editable palladium-based bioorthogonal nanoplatform, consisting of CRISPR/Cas9 gene editing system-linked Pd nanoclusters, and a hyaluronic acid surface layer (HBPdC). This HBPdC nanoplatform exhibited satisfactory tumor-targeting efficiency and triggered Fenton-like reactions in the tumor microenvironment to generate reactive oxygen species for chemodynamic therapy and macrophage M1 polarization, which directly eliminated tumor cells, and stimulated the antitumor response of macrophages. HBPdC could reprogram tumor cells through gene editing to reduce the expression of CD47 and adipocyte plasma membrane-associated protein, thereby promoting their recognition and phagocytosis by macrophages. Moreover, HBPdC induced the activation of sequestered prodrugs via bioorthogonal catalysis, enabling chemotherapy and thereby enhancing tumor cell death. Importantly, the Pd nanoclusters of HBPdC were sufficiently cleared through basic metabolic pathways, confirming their biocompatibility and biosafety. Therefore, by promoting macrophage phagocytosis, the HBPdC system developed herein represents a highly promising antitumor toolset for cancer therapy applications.

Neuronavigated repetitive transcranial magnetic stimulation improves depression, anxiety and motor symptoms in Parkinson's disease.

Background: Repetitive transcranial magnetic stimulation (rTMS) is a potential treatment option for Parkinson's disease patients with depression (DPD), but conflicting results in previous studies have questioned its efficacy. Method: To investigate the safety and efficacy of neuronavigated high-frequency rTMS at the left DLPFC in DPD patients, we conducted a randomized, double-blind, sham-controlled study (NCT04707378). Sixty patients were randomly assigned to either a sham or active stimulation group and received rTMS for ten consecutive days. The primary outcome was HAMD, while secondary outcomes included HAMA, MMSE, MoCA and MDS-UPDRS-III. Assessments were performed at baseline, immediately after treatment, 2 weeks, and 4 weeks post-treatment. Results: The GEE analysis showed that the active stimulation group had significant improvements in depression, anxiety, and motor symptoms at various time points. Specifically, there were significant time-by-group interaction effects in depression immediately after treatment (ß, -4.34 [95% CI, -6.90 to -1.74; P = 0.001]), at 2 weeks post-treatment (ß, -3.66 [95% CI, -6.43 to -0.90; P = 0.010]), and at 4 weeks post-treatment (ß, -4.94 [95% CI, -7.60 to -2.29; P < 0.001]). Similarly, there were significant time-by-group interaction effects in anxiety at 4 weeks post-treatment (ß, -2.65 [95% CI, -4.96 to -0.34; P = 0.024]) and in motor symptoms immediately after treatment (ß, -5.72 [95% CI, -9.10 to -2.34; P = 0.001] and at 4 weeks post-treatment (ß, -5.43 [95% CI, -10.24 to -0.61; P = 0.027]). Conclusion: The study suggested that neuronavigated high-frequency rTMS at left DLPFC is effective for depression, anxiety, and motor symptoms in PD patients.

The Association of the Glymphatic Function with Parkinson's Disease Symptoms: Neuroimaging Evidence from Longitudinal and Cross-Sectional Studies.

OBJECTIVE: Emerging pathological evidence suggests that there is an association between glymphatic dysfunction and the progression of Parkinson's disease (PD). However, the clinical evidence of this association remains lacking. METHODS: In this study, the index for diffusion tensor image analysis along the perivascular space (ALPS index) was calculated to evaluate glymphatic function. RESULTS: Overall, 289 patients with PD were enrolled in the cross-sectional study. The ALPS index was found to be negatively correlated with age, disease severity, and dyskinesia. In the longitudinal study, the information on a total of 95 PD patients with 5-year follow-up examinations was collected from the Parkinson's Progression Marker Initiative, 33 of which were classified into the low ALPS index group, and all others were classified into the mid-high ALPS index group based on the first tertile of the baseline ALPS index. The results of longitudinal regression indicated that there was a significant main group effect on autonomic dysfunction, as well as on activities of daily living. In addition, the low ALPS index group had faster deterioration in MDS-UPDRS part III and part II, Symbol Digit Modalities Test and Hopkins Verbal Learning Test. Path analysis showed that ALPS index acted as a significant mediator between tTau/ Aß1-42 and cognitive change in the Symbol Digit Modalities Test score at year 4 and year 5. INTERPRETATION: The ALPS index, an neuroimaging marker of glymphatic function, is correlated with PD disease severity, motor symptoms, and autonomic function, and is predictive of faster deterioration in motor symptoms and cognitive function. Additionally, glymphatic function may mediate the pathological role of toxic protein in cognitive decline. ANN NEUROL 2023;94:672-683.

LncRNA landscape and associated ceRNA network in placental villus of unexplained recurrent spontaneous abortion.

BACKGROUND: Unexplained recurrent spontaneous abortion (URSA) is one of the most challenging conditions frustrates women of childbearing age profoundly. The gene expression patterns and biological characteristics of placental villus in patients with URSA remain largely unknown. The aim of our study was to identify potential lncRNAs as well as their action mechanisms in URSA. METHOD: The ceRNA microarray was used to identify the mRNA and lncRNA expression profiles of URSA patients and normal pregnancy. Functional enrichment analyses for differentially expressed mRNAs in URSA were performed. Protein-protein interaction analysis of differentially expressed mRNAs was performed to identify hub genes and key modules. Subsequently, the co-dysregulated ceRNA network of URSA was established, and the enrichment analyses for the mRNAs in the ceRNA network was implemented. qRT-PCR was performed to validated the expression of key ENST00000429019 and mRNAs in URSA. RESULTS: We found that URSA placental villus have distinct mRNA and lncRNA expression profiles through ceRNA microarray, with a total of 347 mRNAs and 361 lncRNAs differentially expressed compared with controls. The functional enrichment analysis revealed that ncRNA processing, DNA replication, cell cycle, apoptosis, cytokine-mediated signaling pathway, ECM-receptor interaction were the potentially disrupted pathways in URSA patients. Then we constructed a co-dysregulated ceRNA network and found differentially expressed mRNAs were regulated by a small fraction of hub lncRNAs. Finally, we found a key network of ENST00000429019 and three cell proliferation or apoptosis related key mRNAs (CDCA3, KIFC1, NCAPH), and validated their expression and regulation in tissue and cellular levels. CONCLUSIONS: This study identified a key ceRNA network, which might take part in URSA and correlate with cell proliferation and apoptosis. Optimistically, this study may deepen our apprehensions about the underlying molecular and biological causes of URSA and provide an important theoretical basis for future therapeutic strategies for patients with URSA.

Renin-angiotensin system blockers affect cognitive decline in Parkinson's disease: The PPMI dataset.

OBJECTIVE: To explore the potential clinical effects of renin-angiotensin system blocker (RASB, angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs)) in patients from the Parkinson's Progress Marker Initiative (PPMI) study database. METHODS: One hundred and seven untreated, newly diagnosed PD patients with hypertension, from the PPMI were included. We measured cognitive performance, biomarkers in CSF, and magnetic resonance imaging (MRI) during the five follow-up years for patients exposed or not to renal-angiotensin system blockers. Sixteen PD patients with hypertension underwent [18F]florbetaben positron emission tomography (PET) scanning. SUVRs of region of interest (ROI) were calculated and compared within different groups. RESULT: Treatment with ARBs but not ACEIs improved global cognitive function evaluated by MoCA score in PD patients with hypertension compared to other hypertensive medicines up to 5 years follow up. Specifically, ARBs improved visuospatial, memory, executive abilities, processing speed attention test scores in PD. There was no significant impact of ARBs on α-syn, tau, Aß in CSF. RASBs reduced [18F] florbetaben uptake in cortex and subcortex nuclei in the brain. CONCLUSIONS: These results show potential protective effect with ARBs in cognitive impairment of parkinson's disease with hypertension.

LARS2 Regulates Apoptosis via ROS-Mediated Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Ovarian Granulosa Cells.

Several studies have indicated that mutations of LARS2 are associated with premature ovarian insufficiency (POI). However, the pathogenic mechanism of LARS2 in POI has not been reported yet. In the present study, the expression levels of LARS2 and E2F1 in granulosa cells (GCs) of POI patients were examined. CCK-8 and Edu assay were performed to determine the effect of LARS2 on cell proliferation. Apoptosis rate, mitochondrial membrane potential, reactive oxygen species (ROS), and cytoplasm Ca2+ levels were analyzed by flow cytometry. Western blot was conducted to evaluate the expression level of genes affected by LARS2. Transmission electron microscopy (TEM) was used to observe mitochondrial structure in GCs. Chromatin immunoprecipitation (ChIP) was used to evaluate the regulatory effect of E2F1 on Mfn-2 expression. Our results showed that LARS2 expression was downregulated in GCs of POI patients. Silencing of LARS2 inhibited cell proliferation and promoted the apoptosis of GCs. Meanwhile, LARS2 knockdown could induce mitochondrial dysfunction and accumulation of ROS levels. Moreover, ROS was found to be involved in the antiproliferation, proapoptotic, and endoplasmic reticulum (ER) stress effects of LARS2 knockdown. Furthermore, we also found that the expression level of E2F1 was positively correlated with LARS2. In addition, E2F1 could bind at the -61/-46 region of Mfn-2 promoter and regulated MFN-2 transcription. These findings demonstrated that LARS2 could promote the expression of E2F1. E2F1 mediated the effect of LARS2 on Mfn-2 expression via targeting the promoter region of Mfn-2, in which subsequently regulated cell proliferation and apoptosis, which resulted in the etiology of POI. This study will provide useful information for further investigations on the LARS2 in the occurrence of POI.

An interrelated CataFlower enzyme system for sensitively monitoring sweat glucose.

An accurate measurement of sweat glucose is a promising alternative to invasive finger prick blood test, and may provide effective self-monitoring of blood glucose with good patient compliance. Herein, an interrelated catalytic enzyme system has been developed, termed as CataFlower, which is composed of nanoflower MoS2 (peroxidase) decorated with GOx (glucose oxidase) and MnO2 (oxygen generator), and exhibits synergistic oxidative capability for sensitively monitoring sweat glucose. CataFlower can not only generate oxygen in situ to maximize GOx activity, but promote peroxidase-triggered H2O2 oxidation of methylene blue, resulting in sensitive colorimetric detection of glucose. We identify that CataFlower can precisely detect glucose with a detection limit of 10 µM, allowing for measuring glucose levels in different biological samples, such as blood and urine. Particularly, CataFlower is capable of monitoring dynamic changes in sweat glucose with high sensitivity and accuracy during exercise. Therefore, CataFlower provides a stepping stone to eliminate invasive blood tests, significantly improving the diagnosis and management of diabetes mellitus.

Identifying urotropine derivatives as co-donors of formaldehyde and nitric oxide for improving antitumor therapy.

A pharmacophore integration strategy was utilized to develop the first co-donor of formaldehyde and nitric oxide (FANO), composed of urotropine derived nitramine/nitrosamine. FANO simultaneously generated formaldehyde and nitric oxide on-demand, resulting in synergistic anticancer effects. Importantly, liposomal formulation of FANO effectively inhibited tumor growth with minimal side-effects, providing a potent combined nitric oxide therapy for malignancy.

Identifying Parkinson's disease with mild cognitive impairment by using combined MR imaging and electroencephalogram.

OBJECTIVES: To analyse the changes of quantitative electroencephalogram (qEEG) and cortex structural magnetic resonance (MR) imaging in Parkinson's disease with mild cognitive impairment (PD-MCI) and to explore the "composite marker"-based machine learning model in identifying PD-MCI. METHODS: Retrospective analysis of patients with PD identified 36 PD-MCI and 35 PD with normal cognition (PD-NC). QEEG features of power spectrum and structural MR features of cortex based on surface-based morphometry (SBM) were extracted. Support vector machine (SVM) was established using combined features of structural MR and qEEG to identify PD-MCI. Feature importance evaluation algorithm of mean impact value (MIV) was established to sort the vital characteristics of qEEG and structural MR. RESULTS: Compared with PD-NC, PD-MCI showed a statistically significant difference in 5 leads and waves of qEEG and 7 cortical region features of structural MR. The SVM model based on these qEEG and structural MR features yielded an accuracy of 0.80 in the training set and had a high prediction accuracy of 0.80 in the test set (sensitivity was 0.78, specificity was 0.83, area under the receiver operating characteristic curve was 0.77), which was higher than the model built by the feature separately. QEEG features of theta wave in C3 had a marked impact on the model for classification according to the MIV algorithm. CONCLUSIONS: PD-MCI is characterized by widespread structural and EEG abnormality. "Composite markers" could be valuable for the individualized diagnosis of PD-MCI by machine learning. KEY POINTS: • Explore the brain abnormalities in Parkinson's disease with mild cognitive impairment by using the quantitative electroencephalogram and cortex structural MR simultaneously. • Multimodal features based support vector machine for identifying Parkinson's disease with mild cognitive impairment has an acceptable performance. • Theta wave in C3 is the most influential feature of qEEG and cortex structure MR imaging in identifying Parkinson's disease with mild cognitive impairment using support vector machine.

Alterations in intrinsic functional networks in Parkinson's disease patients with depression: A resting-state functional magnetic resonance imaging study.

AIMS: The aim of this research was to investigate the alterations in functional brain networks and to assess the relationship between depressive impairment and topological network changes in Parkinson's disease (PD) patients with depression (DPD). METHODS: Twenty-two DPD patients, 23 PD patients without depression (NDPD), and 25 matched healthy controls (HCs) were enrolled. All participants were examined by resting-state functional magnetic resonance imaging scans. Graph theoretical analysis and network-based statistic methods were used to analyze brain network topological properties and abnormal subnetworks, respectively. RESULTS: The DPD group showed significantly decreased local efficiency compared with the HC group (P = .008, FDR corrected). In nodal metrics analyses, the degree of the right inferior occipital gyrus (P = .0001, FDR corrected) was positively correlated with the Hamilton Depression Rating Scale scores in the DPD group. Meanwhile, the temporal visual cortex, including the bilateral middle temporal gyri and right inferior temporal gyrus in the HC and NDPD groups and the left posterior cingulate gyrus in the NDPD group, was defined as hub region, but not in the DPD group. Compared with the HC group, the DPD group had extensive weakening of connections between the temporal-occipital visual cortex and the prefrontal-limbic network. CONCLUSIONS: These results suggest that PD depression is associated with disruptions in the topological organization of functional brain networks, mainly involved the temporal-occipital visual cortex and the posterior cingulate gyrus and may advance our current understanding of the pathophysiological mechanisms underlying DPD.

The tumor suppressor Zinc finger protein 471 suppresses breast cancer growth and metastasis through inhibiting AKT and Wnt/ß-catenin signaling.

BACKGROUND: Zinc-finger protein 471 (ZNF471) is a member of the Krüppel-associated box domain zinc finger protein (KRAB-ZFP) family. ZNF471 is methylated in squamous cell carcinomas of tongue, stomach and esophageal. However, its role in breast carcinogenesis remains elusive. Here, we studied its expression, functions, and molecular mechanisms in breast cancer. METHODS: We examined ZNF471 expression by RT-PCR and qPCR. Methylation-specific PCR determined its promoter methylation. Its biological functions and related molecular mechanisms were assessed by CCK-8, clonogenicity, wound healing, Transwell, nude mice tumorigenicity, flow cytometry, BrdU-ELISA, immunohistochemistry and Western blot assays. RESULTS: ZNF471 was significantly downregulated in breast cell lines and tissues due to its promoter CpG methylation, compared with normal mammary epithelial cells and paired surgical-margin tissues. Ectopic expression of ZNF471 substantially inhibited breast tumor cell growth in vitro and in vivo, arrested cell cycle at S phase, and promoted cell apoptosis, as well as suppressed metastasis. Further knockdown of ZNF471 verified its tumor-suppressive effects. We also found that ZNF471 exerted its tumor-suppressive functions through suppressing epithelial-mesenchymal transition, tumor cell stemness and AKT and Wnt/ß-catenin signaling. CONCLUSIONS: ZNF471 functions as a tumor suppressor that was epigenetically inactivated in breast cancer. Its inhibition of AKT and Wnt/ß-catenin signaling pathways is one of the mechanisms underlying its anti-cancer effects.

Effect of Combined Statin and Antihypertensive Therapy in Patients with Hypertension: A Systematic Review and Meta-Analysis.

INTRODUCTION: This meta-analysis aimed to explore the preventive effects of combined statin and antihypertensive therapy on major cardiovascular outcomes in patients with hypertension. METHODS: PubMed, Embase, and the Cochrane Library databases and reference lists of published studies were systematically searched throughout October 9, 2019. Studies designed as randomized controlled trials and investigating the effects of combined statin and antihypertensive therapy versus antihypertensive therapy alone were included. Data abstraction and quality of included studies were assessed by 2 independent authors. The summary results were calculated using relative risks (RRs) with 95% CIs employing a random-effects model. RESULTS: A total of 8 randomized controlled trials including 38,618 patients were finally enrolled. The summary RRs indicated that the combined therapy significantly reduced the risk of major adverse cardiovascular events compared with antihypertensive therapy alone (RR 0.79; 95% CI 0.71-0.88; p < 0.001). Furthermore, the patients in the combined therapy group also experienced less myocardial infarction (RR 0.67; 95% CI 0.53-0.84; p = 0.001) and stroke risks (RR 0.82; 95% CI 0.72-0.94; p = 0.005), while no significant difference was observed between combined therapy and antihypertensive therapy alone regarding cardiac death (RR 0.96; 95% CI 0.84-1.08; p = 0.465) and all-cause mortality (RR 0.95; 95% CI 0.86-1.04; p = 0.277). CONCLUSION: These findings suggested that combined statin and antihypertensive therapy was associated with more cardiovascular benefits compared with antihypertensive therapy alone.

An SBM-based machine learning model for identifying mild cognitive impairment in patients with Parkinson's disease.

OBJECTIVE: To identify Parkinson's disease with mild cognitive impairment (PD-MCI) through surface-based morphometry (SBM) based machine learning model. METHODS: 93 patients with parkinson's disease (35 PD with normal cognition, 58 PD-MCI) were examined, obtaining 276 SBM variables per subject. 20 healthy control subjects were used as the reference. After extracting features with statistically significance, support vector machine (SVM) model with grid search method was applied to identify patients with PD-MCI. Accuracy, matthews correlation coefficient (MCC), receiver operating characteristic curve (ROC), precision-recall curve (PR), AUC-ROC, AUC-PR and leave-one-out cross validation (LOOCV) strategy were employed for model evaluation. RESULTS: PD-MCI is characterized by widespread structural abnormality. SVM model with SBM features achieved an accuracy of 80.00% and area under the ROC of 0.86 for identifying PD-MCI. MCC, AUC-PR, and LOOCV classification accuracy were 0.56, 0.89, and 78.08%, respectively. CONCLUSION: Automatic identification of PD-MCI could be realized by SBM-based machine learning model.

Nanosized Phase-Changeable "Sonocyte" for Promoting Ultrasound Assessment.

Despite the ability of microbubble contrast agents to improve ultrasound diagnostic performance, their application potential is limited due to low stability, fast clearance, and poor tissue permeation. This study presents a promising nanosized phase-changeable erythrocyte (Sonocyte), composed of liposomal dodecafluoropentane coated with multilayered red blood cell membranes (RBCm), for improving ultrasound assessments. Sonocyte is the first RBCm-functionalized ultrasound contrast agent with uniform nanosized morphology, and exhibits good stability, systemic circulation, target-tissue accumulation, and even ultrasound-responsive phase transition, thereby satisfying the inherent requirement of ultrasound imaging. It is identified that Sonocyte displays similar sensitivity as microbubble SonoVue, a clinical ultrasound contrast agent, for effectively detecting normal parenchyma and hepatic necrosis. Importantly, compared with SonoVue lacking of ability to detect tumors, Sonocyte can identify tumors with high sensitivity and specificity due to superior tumor accumulation and penetration. Therefore, Sonocyte exhibits superior capabilities over SonoVue, endowing with a great clinical application potential.