Long-term haplodeficency of DSPP causes temporomandibular joint osteoarthritis in mice.

BACKGROUND: Extracellular matrix (ECM) protein malfunction or defect may lead to temporomandibular joint osteoarthritis (TMJ OA). Dentin sialophophoprotein (DSPP) is a mandibular condylar cartilage ECM protein, and its deletion impacted cell proliferation and other extracellular matrix alterations of postnatal condylar cartilage. However, it remains unclear if long-term loss of function of DSPP leads to TMJ OA. The study aimed to test the hypothesis that long-term haploinsufficiency of DSPP causes TMJ OA. MATERIALS AND METHODS: To determine whether Dspp+/- mice exhibit TMJ OA but no severe tooth defects, mandibles of wild-type (WT), Dspp+/-, and Dspp homozygous (Dspp-/-) mice were analyzed by Micro-computed tomography (micro-CT). To characterize the progression and possible mechanisms of osteoarthritic degeneration over time in Dspp+/- mice over time, condyles of Dspp+/- and WT mice were analyzed radiologically, histologically, and immunohistochemically. RESULTS: Micro-CT and histomorphometric analyses revealed that Dspp+/- and Dspp-/- mice had significantly lower subchondral bone mass, bone volume fraction, bone mineral density, and trabecular thickness compared to WT mice at 12 months. Interestingly, in contrast to Dspp-/- mice which exhibited tooth loss, Dspp+/- mice had minor tooth defects. RNA sequencing data showed that haplodeficency of DSPP affects the biological process of ossification and osteoclast differentiation. Additionally, histological analysis showed that Dspp+/- mice had condylar cartilage fissures, reduced cartilage thickness, decreased articular cell numbers and severe subchondral bone cavities, and with signs that were exaggerated with age. Radiographic data showed an increase in subchondral osteoporosis up to 18 months and osteophyte formation at 21 months. Moreover, Dspp+/- mice showed increased distribution of osteoclasts in the subchondral bone and increased expression of MMP2, IL-6, FN-1, and TLR4 in the mandibular condylar cartilage. CONCLUSIONS: Dspp+/- mice exhibit TMJ OA in a time-dependent manner, with lesions in the mandibular condyle attributed to hypomineralization of subchondral bone and breakdown of the mandibular condylar cartilage, accompanied by upregulation of inflammatory markers.

MicroRNA164 Affects Plant Responses to UV Radiation in Perennial Ryegrass.

Increasing the ultraviolet radiation (UV) level, particularly UV-B due to damage to the stratospheric ozone layer by human activities, has huge negative effects on plant and animal metabolism. As a widely grown cool-season forage grass and turfgrass in the world, perennial ryegrass (Lolium perenne) is UV-B-sensitive. To study the effects of miR164, a highly conserved microRNA in plants, on perennial ryegrass under UV stress, both OsmiR164a overexpression (OE164) and target mimicry (MIM164) transgenic perennial ryegrass plants were generated using agrobacterium-mediated transformation, and UV-B treatment (~600 µw cm-2) of 7 days was imposed. Morphological and physiological analysis showed that the miR164 gene affected perennial ryegrass UV tolerance negatively, demonstrated by the more scorching leaves, higher leaf electrolyte leakage, and lower relative water content in OE164 than the WT and MIM164 plants after UV stress. The increased UV sensitivity could be partially due to the reduction in antioxidative capacity and the accumulation of anthocyanins. This study indicated the potential of targeting miR164 and/or its targeted genes for the genetic manipulation of UV responses in forage grasses/turfgrasses; further research to reveal the molecular mechanism underlying how miR164 affects plant UV responses is needed.

Advances in the Design of Functional Cellulose Based Nanopesticide Delivery Systems.

The advancement of science and technology, coupled with the growing environmental consciousness among individuals, has led to a shift in pesticide development from traditional methods characterized by inefficiency and misuse toward a more sustainable and eco-friendly approach. Cellulose, as the most abundant natural renewable resource, has opened up a new avenue in the field of biobased drug carriers by developing cellulose-based drug delivery systems. These systems offer unique advantages in terms of deposition rate enhancement, modification facilitation, and environmental impact reduction when designing nanopesticides. Consequently, their application in the field of nanoscale pesticides has gained widespread recognition. The present study provides a comprehensive review of cellulose modification methods, carrier types for cellulose-based nanopesticides delivery systems (CPDS), and various stimulus-response factors influencing pesticide release. Additionally, the main challenges in the design and application of CPDS are summarized, highlighting the immense potential of cellulose-based materials in the field of nanopesticides.

Fibrosis and steatotic liver disease in US adolescents according to the new nomenclature.

OBJECTIVE: To apply the new nomenclature for steatotic liver diseases (SLD), replacing nonalcoholic fatty liver disease (NAFLD) with metabolic dysfunction-associated steatotic liver disease (MASLD), in adolescents using National Health and Nutrition Examination Survey (NHANES) data. METHODS: Among 1410 adolescents (12-19 years) in NHANES (2017-March, 2020), the controlled attenuation parameter (CAP) of transient elastography (TE) was used to define steatosis and fibrosis (TE ≥ 7.4 kPa). Obesity and alanine aminotransferase (ALT) ≥ 80 U/L were used to identify adolescents qualifying for hepatology referral according to practice guidelines. NAFLD was defined as liver steatosis without a specific exposure; it has no cardiometabolic risk factor requirement, unlike MASLD. RESULTS: Steatosis (yes/no) is the first decision point in the new diagnostic protocol; however, criteria for steatosis are undefined. At the supplier (EchoSens)-recommended CAP threshold of 240 dB/m, 30.5% (95% confidence interval [CI]: 27.1%-34.0%) of adolescents had SLD and about 85% of adolescents with NAFLD met criteria for MASLD. The other 15% would receive an ambiguous diagnosis of either cryptogenic SLD or possible MASLD. At higher CAP thresholds, MASLD/NAFLD concordance increased and approached 100%. Among adolescents with MASLD-fibrosis, only 8.8% (95% CI: 0%-19.3%) had overweight/obese and ALT ≥ 80 U/L. CONCLUSIONS: The new nomenclature highlights the high prevalence of liver steatosis. At the CAP threshold of 240 dB/m, however, approximately 15% of adolescents would receive an ambiguous diagnosis, which could lead to confusion and worry. Fewer than 10% of adolescents with MASLD-fibrosis had overweight/obese and ALT ≥ 80 U/L. Revised guidelines are needed to ensure that the other 90% receive appropriate referral and liver disease care.

Bayesian network models identify cooperative GPCR:G protein interactions that contribute to G protein coupling.

Cooperative interactions in protein-protein interfaces demonstrate the interdependency or the linked network- like behavior and their effect on the coupling of proteins. Cooperative interactions also could cause ripple or allosteric effects at a distance in protein-protein interfaces. Although they are critically important in protein-protein interfaces, it is challenging to determine which amino acid pair interactions are cooperative. In this work we have used Bayesian network modeling, an interpretable machine learning method, combined with molecular dynamics trajectories to identify the residue pairs that show high cooperativity and their allosteric effect in the interface of G protein coupled receptor (GPCR) complexes with Gα subunits. Our results reveal six GPCR:Gα contacts that are common to the different Gα subtypes and show strong cooperativity in the formation of interface. Both the C-terminus helix5 and the core of the G protein are codependent entities and play an important role in GPCR coupling. We show that a promiscuous GPCR coupling to different Gα subtypes, makes all the GPCR:Gα contacts that are specific to each Gα subtype (Gαs, Gαi and Gαq). This work underscores the potential of data-driven Bayesian network modeling in elucidating the intricate dependencies and selectivity determinants in GPCR:G protein complexes, offering valuable insights into the dynamic nature of these essential cellular signaling components.

A global dataset of terrestrial evapotranspiration and soil moisture dynamics from 1982 to 2020.

Quantifying terrestrial evapotranspiration (ET) and soil moisture dynamics accurately is crucial for understanding the global water cycle and surface energy balance. We present a novel, long-term dataset of global ET and soil moisture derived from the newly developed Simple Terrestrial Hydrosphere model, version 2 (SiTHv2). This ecohydrological model, driven by multi-source satellite observations and hydrometeorological variables from reanalysis data, provides daily global ET-related estimates (e.g., total ET, plant transpiration, soil evaporation, intercepted evaporation) and three-layer soil moisture dynamics at a 0.1° spatial resolution. Validation with in-situ measurements and comparisons with mainstream global ET and soil moisture products demonstrate robust performance of SiTHv2 in both magnitude and temporal dynamics of ET and soil moisture at multiple scales. The comprehensive water path characterization in the SiTHv2 model makes this seamless dataset particularly valuable for studies requiring synchronized water budget and vegetation response to water constraints. With its long-term coverage and high spatiotemporal resolution, the SiTHv2-derived ET and soil moisture product will be suitable to support analyses related to the hydrologic cycle, drought assessment, and ecosystem health.

Identification of Hsp20 gene family in Malus domestica and functional characterization of Hsp20 class I gene MdHsp18.2b.

Heat shock protein 20 (Hsp20) is a small molecule heat shock protein that plays an important role in plant growth, development, and stress resistance. Little is known about the function of Hsp20 family genes in apple (Malus domestica). Here, we performed a genome-wide analysis of the apple Hsp20 gene family, and a total of 49 Hsp20s genes were identified from the apple genome. Phylogenetic analysis revealed that the 49 genes were divided into 11 subfamilies, and MdHsp18.2b, a member located in the CI branch, was selected as a representative member for functional characterization. Treatment with NaCl and Botryosphaeria dothidea (B. dothidea), the causal agent of apple ring rot disease, significantly induced MdHsp18.2b transcription level. Further analysis revealed that overexpressing MdHsp18.2b reduced the resistance to salt stress but enhanced the resistance to B. dothidea infection in apple calli. Moreover, MdHsp18.2b positively regulated anthocyanin accumulation in apple calli. Physiology assays revealed that MdHsp18.2b promoted H2O2 production, even in the absence of stress factors, which might contribute to its functions in response to NaCl and B. dothidea infection. Hsps usually function as homo- or heterooligomers, and we found that MdHsp18.2b could form a heterodimer with MdHsp17.9a and MdHsp17.5, two members from the same branch with MdHsp18.2b in the phylogenetic tree. Therefore, we identified 49 Hsp20s genes from the apple genome and found that MdHsp18.2b was involved in regulating plant resistance to salt stress and B. dothidea infection, as well as in regulating anthocyanin accumulation in apple calli.

Highly Sensitive and Stable Flexible Smart Sensors Based on Commercial Carbon Fiber Powder Inks.

With the fast development of the smart lifestyle in recent years, simple and flexible body condition monitoring has become more and more important. However, currently, commercially available motion-sensing devices always lack flexibility or at a high cost. This article has fully explored the merits of a commercial and easily available material of carbon fiber powder (CFP) and prepared CFP-based screen printing inks. This conductive ink can be directly and quickly printed onto a variety of different flexible common substrates, such as paper, cotton fabrics, etc., to prepare flexible sensors. At the same time, as a result of the good photothermal performance and conductivity of CFP, the printed flexible sensors have fast and stable performance on thermal and human motion detection. The use of CFP as the smart element to construct a wearable device will offer a choice for the intelligent industry.

First-Trimester Triglyceride-Glucose Index and Triglyceride/High-Density Lipoprotein Cholesterol are Predictors of Gestational Diabetes Mellitus Among the Four Surrogate Biomarkers of Insulin Resistance.

Purpose: This study seeks to assess the potential of early pregnancy Triglyceride Glucose Index (TyG), triglyceride to High-Density Lipoprotein Cholesterol ratio (TG/HDL-c), Low-Density Lipoprotein Cholesterol to High-Density Lipoprotein Cholesterol ratio (LDL-C/HDL-C), and Total Cholesterol to High-Density Lipoprotein Cholesterol ratio (TC/HDL-C) in predicting Gestational Diabetes Mellitus (GDM). Patients and Methods: A total of 1073 adults singleton pregnant women were enrolled from June 2017 to September 2019. Complete anthropometric data and lipid profiles were measured in the first trimester (before 12 weeks gestation) and a 75g oral glucose tolerance test (OGTT) at 24-28 weeks was performed. Based on OGTT results, participants were categorised into Normal Glucose Tolerance (NGT) group (n=872) and GDM group (n=201). General data, laboratory test results, and surrogate insulin resistance indicators such as TyG index, TG/HDL-C, LDL-C/HDL-C, and TC/HDL-C were documented and compared. To compare differences between the two groups, t-test was used, Spearman correlation analysis and linear regression analysis were performed to establish associations between these indicators and insulin resistance in GDM. Receiver Operating Characteristic (ROC) curves were generated to compare the thresholds of these indicators for predicting GDM during pregnancy and to quantify overall diagnostic accuracy. Results: Individuals with GDM had higher TyG, TG/HDL-C, and LDL-C/HDL-C levels (P < 0.001), but with no significant difference observed in TC/HDL-C. All four ratios were positively correlated with Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), yet only TyG emerged as an independent risk factor for HOMA-IR. The Area under the Curve (AUC) of TyG index (0.692) was comparable to that of HOMA-IR (0.703). The cut-off points for TyG index, TG/HDL-C, and HOMA-IR in predicting GDM were 7.088, 0.831, and 1.8, respectively. HOMA-IR exhibited the highest sensitivity (79.1%), while TyG index (64.3%) and TG/HDL-C ratio (64.3%) demonstrated better specificity compared to HOMA-IR (56.3%). LDL-C/HDL-C and TC/HDL-C offered no discernible predictive advantage. Conclusion: Early pregnancy TyG index and TG/HDL-C can aid in identifying pregnant women at risk for GDM, potentially facilitating early and effective intervention to improve prognosis. TyG index exhibited superior predictive capability compared to TG/HDL-C.

Scalable Fabrication of Ionic-Conductive Covalent Organic Framework Fibers for Capturing of Sustainable Osmotic Energy.

High-performance covalent organic framework (COF) fibers are demanded for an efficient capturing of blue osmotic power because of their excellent durability, simple integration, and large scalability. However, the scalable production of COF fibers is still very challenging due to the poor solubility and fragile structure of COFs. Herein, for the first time, it is reported that COF dispersions can be continuously processed into macroscopic, meter-long, and pure COF fibers using a wet spinning approach. The two presented COF fibers can be directly used for capturing of osmotic energy, avoiding the production of composite materials that require other additives and face challenges such as phase separation and environmental issues induced by the additives. A COF fiber exhibits power densities of 70.2 and 185.3 W m-2 at 50-fold and 500-fold salt gradients, respectively. These values outperform those of most reported systems, which indicate the high potential of COF fibers for capturing of blue osmotic energy.

Potential Common Mechanisms of Cytotoxicity Induced by Organophosphorus Pesticides via NLRP3 Inflammasome Activation.

The Multi-Threat Medical Countermeasure (MTMC) technique is crucial for developing common biochemical signaling pathways, molecular mediators, and cellular processes. This study revealed that the Nod-like receptor 3 (NLRP3) inflammasome pathway may be a significant contributor to the cytotoxicity induced by various organophosphorus pesticides (OPPs). The study demonstrated that exposure to six different types of OPPs (paraoxon, dichlorvos, fenthion, dipterex, dibrom, and dimethoate) led to significant cytotoxicity in BV2 cells, which was accompanied by increased expression of NLRP3 inflammasome complexes (NLRP3, ASC, Caspase-1) and downstream inflammatory cytokines (IL-1ß, IL-18), in which the order of cytotoxicity was dichlorvos > dipterex > dibrom > paraoxon > fenthion > dimethoate, based on the IC50 values of 274, 410, 551, 585, 2,158, and 1,527,566 µM, respectively. The findings suggest that targeting the NLRP3 inflammasome pathway could be a potential approach for developing broad-spectrum antitoxic drugs to combat multi-OPPs-induced toxicity. Moreover, inhibition of NLRP3 efficiently protected the cells against cytotoxicity induced by these six OPPs, and the expression of NLRP3, ASC, Caspase-1, IL-1ß, and IL-18 decreased accordingly. The order of NLRP3 affinity for OPPs was dimethoate > paraoxon > dichlorvos > dibrom > (fenthion and dipterex) based on K D values of 89.8, 325, 1,460, and 2,690 µM, respectively. Furthermore, the common molecular mechanism of NLRP3-OPPs was clarified by the presence of toxicity effector groups (benzene ring, nitrogen/oxygen-containing functional group); =O, -O-, or =S (active) groups; and combination residues (Gly271, Asp272). This finding provided valuable insights into exploring the common mechanisms of multiple threats and developing effective therapeutic strategies to prevent OPPs poisoning.

A systematic review and meta-analysis of the association between air pollutants and the incidence of tuberculosis.

Objective: To investigate the association between air pollutants and the incidence of tuberculosis (TB) through a systematic review and meta-analysis, and to provide directions for future research and prevention of TB. Methods: A search was conducted for all literature related to the incidence of TB and air pollution in the database. We screened the retrieved articles and proceeded statistical analyses using random effects models to investigate the relationships between five air pollutants (PM2.5, PM10, SO2, NO2 and O3) and the incidence of TB. Results: The initial search identified 100 pieces of literature and 9 studies met the screening criteria after the screening. The single-day lagged risk ratio (RR) and 95% Confidence Intervals (CIs) for the combined effects estimates are as follows: PM2.5: 1.059 (0.966, 1.160); PM10: 1.000 (0.996, 1.004); SO2: 0.980 (0.954, 1.007); NO2: 1.011 (0.994, 1.027); O3: 0.994 (0.980,1.008). The cumulative lagged results for these five pollutants are listed like this: PM2.5: 1.095 (0.983, 1.219); PM10: 1.035 (1.006, 1.066); SO2: 0.964 (0.830, 1.121); NO2: 1.037 (1.010, 1.065); O3: 0.982 (0.954, 1.010). Conclusion: The single-day lag effects of PM2.5, PM10, SO2, NO2, and O3 are not statistically significantly relevant for the occurrence of TB. However, the cumulative lag results show that both PM10 and NO2 contribute to the prevalence of TB, while the statistical relationship between the cumulative lag effects of PM2.5, SO2, and O3 and the onset of TB remains unknown.

Association between concurrence of multiple risk factors and under-5 mortality: a pooled analysis of data from Demographic and Health Survey in 61 low-and-middle-income countries.

Background: Exposure to multiple risk factors is prevalent in low-and middle-income countries (LMICs), challenging one-directional strategies to address preventable under-5 mortality (U5M). This study aims to assess the associations between concurrence of multiple risk factors and U5M in LMICs. Methods: We extracted data from the Demographic and Health Surveys conducted between 2010 and 2021 across 61 LMICs. Our primary outcome was U5M, defined as deaths from birth to 59 months. Binary logistic regression model was applied to ascertain the association between U5M and a total of 20 critical risk factors. Upon identifying the risk factors demonstrating the strongest associations, we investigated the simultaneous presence of multiple risk factors in each individual and assessed their combined effects on U5M with logistic regression models. Findings: Of the 604,372 under-5 children, 18,166 (3.0%) died at the time of the survey. Unsatisfied family planning needs was the strongest risk factor for U5M (odds ratio [OR]: 2.0, 95% confidence interval [CI]: 1.9-2.1), followed by short birth interval (<18 months; OR: 2.0, 95% CI: 1.9-2.1), small birth size (OR: 2.0, 95% CI: 1.8-2.1), never breastfed or delayed breastfeeding (OR: 2.0, 95% CI: 1.9-2.0), and low maternal education (OR: 1.6, 95% CI: 1.4-1.8). 66.7% (66.6%-66.8%) of the children had 2 or more leading risk factors simultaneously. Simultaneous presence of multiple leading risk factors was significantly associated with elevated risk of U5M and children presenting with all 5 leading risk factors exhibited an exceedingly high risk of U5M (OR: 5.2, 95% CI: 4.3-6.3); a dose-response relationship between the number of risk factors and U5M was also observed-with the increment of numbers of leading risk factors, the U5M showed an increasing trend (p-trend < 0.001). Interpretation: Exposure to multiple risk factors is very common in LMICs and underscores the necessity of developing multisectoral and integrated approaches to accelerate progress in reducing U5M in line with the SDG 3.2. Funding: This research is funded by Research Fund, Vanke School of Public Health, Tsinghua University.

Evaluation the Effect of Anthracyclines on Cardiac Function in Children Lymphoma Survivors by Left Ventricular Myocardial Work.

Anthracycline chemotherapy is associated with the left ventricular (LV) dysfunction, but the conventional echocardiographic parameter is insensitive in detecting subclinical cardiac dysfunction, and the role of echocardiography in children cancer survivors (CCSs) has not been well established. Here, the myocardial work (MW) was employed to evaluate the early effect of the anthracyclines on LV function in children lymphoma survivors, as well as to explore the clinical application value of this modality. 51 children lymphoma survivors treated with anthracyclines were included. During the treatments, the echocardiography was performed at baseline (T0 phase), the 3rd (T1 phase) and 6th (T2 phase) chemotherapeutic cycle, respectively. After that, the conventional echocardiographic parameters, LV global longitudinal strain (GLS), and global myocardial work (GMW) parameters were obtained. Finally, these echocardiographic parameters were compared to distinguish the differences among three groups, and correlation analysis was used to identify relationship between GMW parameters and LV GLS. Compared with the baseline, we found that there are no significant differences for LVEF and other conventional echocardiographic parameters after chemotherapy, but the value of LV lateral E/E' increased at T1 and T2 group. The GLS, global work index, global constructed work, and global work efficiency were decreased, while the global wasted work was increased after chemotherapy (all P < 0.05). The correlation analysis showed that the GLS has significant correlation with GMW parameters (all P < 0.001). The MW, as a new noninvasive echocardiography modality, could be used to quantitatively evaluate the LV MW in children lymphoma survivors treated with anthracyclines, which providing a sensitive method to early detect the children's LV dysfunction after the chemotherapy.

Multiplex dependence analysis of China's interprovincial virtual water based on an ecological network.

The interprovincial circulation of goods and services has formed virtual water flows between regions, which can redistribute water resources. Based on previous virtual water trade research, this study further explored the multiple dependencies of virtual water, i.e., direct, indirect, and complete dependence. This study examined the direct, indirect, and complete dependence of virtual water between provinces in China by constructing multilayer dependence networks and identified the key regions and paths of virtual water trade network. The results showed direct dependence was the densest and had the largest overall dependence degree, but indirect dependence was the most stable and orderly. Second, the dominant provinces were Guangxi, Hunan, Sichuan, Xinjiang, and Anhui, referred to as "core‒five‒region," and the flow relevant to them accounted for approximately 30% of the virtual water. The seven provinces of Shanxi, Zhejiang, Shandong, Hubei, Guangdong, Shaanxi, and Gansu depend both directly and indirectly on the "core‒five‒region." Shanxi and Zhejiang have close direct and indirect dependence, with more than one of the "core‒five‒region." Guangdong was the province with the most direct and indirect input of virtual water from the "core‒five‒region." The study provides a scientific basis for multiregional identification for the collaborative management of water resources in China from the perspective of dependence.

A longitudinal study on the effects of social support on self-stigma, psychiatric symptoms, and personal and social functioning in community patients with severe mental illnesses in China.

BACKGROUND: Few studies have examined whether social support contributes to better consequences among chronic patients with severe mental illnesses (SMI) in their community recovery stage and whether self-stigma would be a mechanism through which social support impacts psychiatric symptoms and personal and social functioning. AIMS: This study aimed to examine prospective associations of social support with long-term self-stigma, psychiatric symptoms, and personal and social functioning, and to investigate whether self-stigma would mediate the associations of social support with psychiatric symptoms and personal and social functioning among patients with SMI. METHODS: A total of 312 persons with SMI (schizophrenia and bipolar disorder) in their community recovery stage participated in the study. Social support, self-stigma, psychiatric symptoms, and personal and social functioning were evaluated at baseline. The follow-up assessment was conducted at 6 months with the baseline measures except for social support. Hierarchical linear regression and mediation analysis were performed. RESULTS: The results showed that baseline social support predicted decreases in stigma (ß = -.115, p = .029) and psychiatric symptoms (ß = -.193, p < .001), and increases in personal and social functioning (ß = .134, p = .008) over 6 months, after adjusting for relevant covariates. Stigma at 6 months partially mediated the association between baseline social support and 6-month psychiatric symptoms (indirect effect: ß = -.043, CI [-0.074, -0.018]). Stigma and psychiatric symptoms at 6 months together mediated the association between baseline social support and 6-month personal and social functioning (indirect effect: ß = .084, 95% CI [0.029, 0.143]). CONCLUSION: It is necessary to provide comprehensive social support services and stigma reduction interventions at the community level to improve the prognosis of SMI.

A Guanidinobenzol-Rich Polymer Overcoming Cascade Delivery Barriers for CRISPR-Cas9 Genome Editing.

The efficient cytosolic delivery of the CRISPR-Cas9 machinery remains a challenge for genome editing. Herein, we performed ligand screening and identified a guanidinobenzol-rich polymer to overcome the cascade delivery barriers of CRISPR-Cas9 ribonucleoproteins (RNPs) for genome editing. RNPs were stably loaded into the polymeric nanoparticles (PGBA NPs) by their inherent affinity. The polymer facilitated rapid endosomal escape of RNPs via a dynamic multiple-step cascade process. Importantly, the incorporation of fluorescence in the polymer helps to identify the correlation between cellular uptake and editing efficiency, increasing the efficiency up to 70% from the initial 30% for the enrichment of edited cells. The PGBA NPs efficiently deliver RNPs for in vivo gene editing via both local and systemic injections and dramatically reduce PCSK9 level. These results indicate that PGBA NPs enable the cascade delivery of RNPs for genome editing, showing great promise in broadening the therapeutic potential of the CRISPR-Cas9 technique.