Association between diabetes mellitus and ossification of the spinal ligament: a systematic review and meta-analysis.

PURPOSE: Ossification of the spinal ligament (OSL) is a spinal disorder characterized by abnormal bone formation in the spinal ligaments. Although clinical studies suggested that diabetes mellitus (DM) was associated with OSL, no consistent conclusion was drawn about the relationship between DM and the onset of OSL. METHODS: Studies with data on DM and OSL were retrieved by searching PubMed, Embase, Web of Science, and Cochrane Library from inception to August 23, 2023. Pooled estimates of odds ratios (ORs) with 95% confidence interval (95% CI) were calculated using random-effects models. Statistical analyses were performed by R 4.2.2 software. RESULTS: A total of 17 studies with 70,945 participants were included. The quantitative findings demonstrated that a higher risk of DM was related to the onset of OSL (OR = 2.19, 95% CI: 1.27-3.79, p = 0.008). Subgroup analysis showed a higher rate of DM in OSL patients from Japan (OR = 3.29, 95% CI: 1.51-7.17, [Formula: see text] = 0.009) than from other regions. Moreover, patients with OSL had a higher rate of DM in age < = 60 group (OR = 3.46, 95% CI: 1.14-10.50, p = 0.035) than age > 60 group (OR = 2.26, 95% CI: 1.07-4.79, p = 0.036). CONCLUSION: DM is significantly associated with an increased risk of developing OSL, especially in Japanese and people under 60 years old. Further studies with more participants were warranted to confirm the findings and provide new insights into the prevention and treatment of OSL.

Interface-reinforced high-capacity fiber cathode for wearable Li-S batteries.

Fiber-shaped Li-S batteries are attractive for constructing smart textiles as flexible power solutions due to their high theoretical specific capacity, flexibility and wearability. However, severe interfacial issues, such as the shuttle effect of polysulfides on the cathode side, lead to capacity decay and poor lifespan of the batteries. Herein, we report a fiber-shaped composite cathode with collaborative interface interactions to maintain electrode integrity and boost electrochemical performance. In this architecture, nanosulfur-polyvinylpyrrolidone (nanoS-PVP) particles are uniformly implanted into the few-layer Ti3C2T x with outstanding electrical conductivity and then coated on aluminum (Al) fiber current collectors. Impressively, nanoS and soluble polysulfides are restricted to the cathode side via synergy physical confinement and chemical adsorption of Ti3C2T x . The PVP chains on the surface of the nanoS prevent the sulfur from agglomeration and bridge the Ti3C2T x by abundant hydrogen bonds. The enhanced interface endows the cathode with excellent mechanical flexibility, good adsorption of polysulfides and fast reaction kinetics. Consequently, the prepared Ti3C2T x /nanoS-PVP@Al cathode exhibits excellent cycling performance (capacity retention of 92.8% after 1000 cycles at 1 C), high-rate capacity (556.2 mAh g-1 at 2.0 C) and high linear capacity (22.9 mAh m-1). Additionally, the fiber-shaped Li-S battery works effectively under deformation and high/low-temperature conditions. It can be integrated into the fabric to power light emitting diodes or charge a smartphone wirelessly.

Opposite effects of soil pH on bacteria and fungi ß diversity in forests at a continental scale.

Soil microbial diversity is crucial for regulating biogeochemical cycles, including soil carbon (C) dynamics and nutrient cycling. However, how climate, plants, and soil properties influence the microbiome in forests remains unclear, especially at the continental scale, hindering us to better understand forest C-climate change feedback. Here, we investigated the spatial patterns of microbial diversity across China's forests and explored the controlling factors of microbial ß diversity and network complexity. Our results showed that soil pH strongly influenced bacterial and fungal ß diversity compared to climate, soil nutrient and plant properties. To further investigate the environmental preference of the microbial networks, we classified the amplicon sequence variants (ASVs) into five groups ranging from acidic to alkaline soils. Co-occurrence network analysis revealed that the topological structure of the bacterial network (e.g., edge and degree) increased with pH and was negatively correlated with ß diversity but not for fungal diversity. Soil fungi exhibited higher ß diversity and network complexity (i.e., degree and betweenness) than bacteria in acidic soils (pH < 5.1), and vice versa in neutral and alkaline soils (pH > 5.5). Within the pH range of 5.1-5.5, the bacterial-fungal network displayed the highest network complexity with the lowest fungal ß diversity, and significant positive correlations were found between fungal ß diversity and soil properties. In addition, bacterial growth in acidic soil (pH < 5.5) showed positive correlations with acid phosphatase (AP), but negative ones with ß-1,4-glucosidase (BG), and vice versa in neutral and alkaline soils (pH > 5.5). Furthermore, 46 bacterial core species were identified, and their abundance had significant correlation with soil pH. These findings highlight the critical role of soil pH in driving soil microbial ß diversity across China's forests and reveal the effects of pH thresholds on changes in the soil microbial network and core species.

Fucoidan improving spinal cord injury recovery: Modulating microenvironment and promoting remyelination.

INTRODUCTION: Excessive neuroinflammation, apoptosis, glial scar, and demyelination triggered by spinal cord injury (SCI) are major obstacles to SCI repair. Fucoidan, a natural marine plant extract, possesses broad-spectrum anti-inflammatory and immunomodulatory effects and is regarded as a potential therapeutic for various diseases, including neurological disorders. However, its role in SCI has not been investigated. METHODS: In this study, we established an SCI model in mice and intervened in injury repair by daily intraperitoneal injections of different doses of fucoidan (10 and 20 mg/kg). Concurrently, primary oligodendrocyte precursor cells (OPCs) were treated in vitro to validate the differentiation-promoting effect of fucoidan on OPCs. Basso Mouse Scale (BMS), Louisville Swim Scale (LSS), and Rotarod test were carried out to measure the functional recovery. Immunofluorescence staining, and transmission electron microscopy (TEM) were performed to assess the neuroinflammation, apoptosis, glial scar, and remyelination. Western blot analysis was conducted to clarify the underlying mechanism of remyelination. RESULTS: Our results indicate that in the SCI model, fucoidan exhibits significant anti-inflammatory effects and promotes the transformation of pro-inflammatory M1-type microglia/macrophages into anti-inflammatory M2-type ones. Fucoidan enhances the survival of neurons and axons in the injury area and improves remyelination. Additionally, fucoidan promotes OPCs differentiation into mature oligodendrocytes by activating the PI3K/AKT/mTOR pathway. CONCLUSION: Fucoidan improves SCI repair by modulating the microenvironment and promoting remyelination.

Risk factors of shunt-dependent hydrocephalus after subarachnoid hemorrhage: a systematic review and meta-analysis based on observational cohort studies.

Shunt dependent hydrocephalus (SDHC) is a common sequel after aneurysmal subarachnoid hemorrhage (aSAH) and factors contributing to the development of SDHC remain obscure. The aim of this study was to identify predictors of SDHC following aSAH. We conducted a systematic review based on the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines. We searched electronic databases including Pubmed, Embase, and Cochrane databases from 1980 through August 2019 for studies on the risk factors of SDHC after aSAH. Inclusion criteria were: (1) SAH and hydrocephalus confirmed by CT or magnetic resonance imaging findings; (2) the odds ratios (ORs) or the relative risk (RR) with 95% confidence interval (95%CI; or crude data that allowed their calculation) were reported; and (3) languages were restricted to English and Chinese. Two independent authors collected the data including study design, characteristics of patients and potential risk factors. Random-effects models were used to estimate weighted mean differences (WMD), relative risks (RR) with corresponding 95% confidence intervals (CI). For analysis with significant heterogeneity, subgroup analyses stratified by study design and geographic area were performed. In all, 37 cohort studies met inclusion criteria. Several factors were associated with SDHC. Infection, acute hydrocephalus, placement of external ventricular drainage, older age, higher Hunt and Hess grade, intraventricular hemorrhage, rebleeding, and mechanical ventilation were associated with greater 2-fold increased risk of SDHC. Vasospasm, female gender, high Fisher grade, preexisting hypertension, aneurysm in posterior location and intracerebral hemorrhage were associated with less than 2-fold increased risk. Treatment modality and diabetes mellitus were not associated with SDHC. SDHC is a multi-factorial disease that is associated with patient and treatment factors. Acknowledgement of these potential factors could help prevent SDHC.

A Review of Advancements and Challenges in Liver Segmentation.

Liver segmentation technologies play vital roles in clinical diagnosis, disease monitoring, and surgical planning due to the complex anatomical structure and physiological functions of the liver. This paper provides a comprehensive review of the developments, challenges, and future directions in liver segmentation technology. We systematically analyzed high-quality research published between 2014 and 2024, focusing on liver segmentation methods, public datasets, and evaluation metrics. This review highlights the transition from manual to semi-automatic and fully automatic segmentation methods, describes the capabilities and limitations of available technologies, and provides future outlooks.

Bioinspired iontronic synapse fibers for ultralow-power multiplexing neuromorphic sensorimotor textiles.

Artificial neuromorphic devices can emulate dendric integration, axonal parallel transmission, along with superior energy efficiency in facilitating efficient information processing, offering enormous potential for wearable electronics. However, integrating such circuits into textiles to achieve biomimetic information perception, processing, and control motion feedback remains a formidable challenge. Here, we engineer a quasi-solid-state iontronic synapse fiber (ISF) comprising photoresponsive TiO2, ion storage Co-MoS2, and an ion transport layer. The resulting ISF achieves inherent short-term synaptic plasticity, femtojoule-range energy consumption, and the ability to transduce chemical/optical signals. Multiple ISFs are interwoven into a synthetic neural fabric, allowing the simultaneous propagation of distinct optical signals for transmitting parallel information. Importantly, IFSs with multiple input electrodes exhibit spatiotemporal information integration. As a proof of concept, a textile-based multiplexing neuromorphic sensorimotor system is constructed to connect synaptic fibers with artificial fiber muscles, enabling preneuronal sensing information integration, parallel transmission, and postneuronal information output to control the coordinated motor of fiber muscles. The proposed fiber system holds enormous promise in wearable electronics, soft robotics, and biomedical engineering.

Vertebral artery injury following combination Jefferson fracture of C1 and Type II odontoid fracture: A case report.

Traumatic posterior atlantoaxial dislocation combined with Jefferson fracture and odontoid process fracture with vertebral artery injury is rare. The management of such injury raises controversial issues and is still open to debate. A 74-year-old Chinese male presented with sustained neck pain and stiffness after falling from height. The patient was neurologically intact. Preoperative radiographs demonstrated a Jefferson burst fracture with a posterior dislocation of the atlantoaxial joints and odontoid process Anderson and D'alonzo type II fracture. A computed tomography angiography (CTA) showed an occluded left vertebral artery. Coil embolization in the proximal portion of the occluded vertebral artery was performed to prevent further cerebral infarction due to distal embolization of the thrombus. Then a second stage occipito-cervical fusion was performed to reconstruct cervical spine stability. A systematic screening of blunt trauma vertebral artery injuries through CTA is required when dealing with upper cervical fracture. For cases with vertebral artery occlusion secondary to cervical spine injury, endovascular treatment preceding cervical spine surgery is a feasible and a safe treatment.

A Highly Stable, Multifunctional Janus Dressing for Treating Infected Wounds.

The limited and unstable absorption of excess exudate is a major challenge during the healing of infected wounds. In this study, a highly stable, multifunctional Janus dressing with unidirectional exudate transfer capacity is fabricated based on a single poly(lactide caprolactone) (PLCL). The success of this method relies on an acid hydrolysis reaction that transforms PLCL fibers from hydrophobic to hydrophilic in situ. The resulting interfacial affinity between the hydrophilic/phobic PLCL fibers endows the Janus structure with excellent unidirectional liquid transfer and high structural stability against repeated stretching, bending, and twisting. Various other functions, including wound status detection, antibacterial, antioxidant, and anti-inflammatory properties, are also integrated into the dressing by incorporating phenol red and epigallocatechin gallate. An in vivo methicillin-resistant Staphylococcus aureus-infected wound model confirms that the Janus dressing, with the capability to remove exudate from the infected site, not only facilitates epithelialization and collagen deposition, but also ensures low inflammation and high angiogenesis, thus reaching an ideal closure rate up to 98.4% on day 14. The simple structure, multiple functions, and easy fabrication of the dressing may offer a promising strategy for treating chronic wounds, rooted in the challenges of bacterial infection, excessive exudate, and persistent inflammation.

Stretchable and Self-Powered Mechanoluminescent Triboelectric Nanogenerator Fibers toward Wearable Amphibious Electro-Optical Sensor Textiles.

Flexible electro-optical dual-mode sensor fibers with capability of the perceiving and converting mechanical stimuli into digital-visual signals show good prospects in smart human-machine interaction interfaces. However, heavy mass, low stretchability, and lack of non-contact sensing function seriously impede their practical application in wearable electronics. To address these challenges, a stretchable and self-powered mechanoluminescent triboelectric nanogenerator fiber (MLTENGF) based on lightweight carbon nanotube fiber is successfully constructed. Taking advantage of their mechanoluminescent-triboelectric synergistic effect, the well-designed MLTENGF delivers an excellent enhancement electrical signal of 200% and an evident optical signal whether on land or underwater. More encouragingly, the MLTENGF device possesses outstanding stability with almost unchanged sensitivity after stretching for 200%. Furthermore, an extraordinary non-contact sensing capability with a detection distance of up to 35 cm is achieved for the MLTENGF. As application demonstrations, MLTENGFs can be used for home security monitoring, intelligent zither, traffic vehicle collision avoidance, and underwater communication. Thus, this work accelerates the development of wearable electro-optical textile electronics for smart human-machine interaction interfaces.

Research trends and hotspots of myositis ossificans: a bibliometric analysis from 1993 to 2022.

Myositis ossificans (MO) is characterized by benign heterotopic ossificans in soft tissues like muscles, which can be classified into nonhereditary MO and fibrodysplasia ossificans progressiva (FOP). Although MO has been studied for decades, no research reviewed and analyzed the features of publications in this field quantitatively and qualitatively. Using bibliometrics tools (bibliometrix R package, VOSviewer, and CiteSpace), we conducted a bibliometric analysis of 1280 articles regarding MO in the Web of Science Core Collection database from 1993 to 2022. The annual number of publications and related research areas in the MO field increased gradually in the past 20 years. The USA contributed the most percentage (42.58%) of articles. The University of Pennsylvania (UPenn) and the Journal Bone published the most articles among all institutions and journals. Kaplan FS and Shore EM from UPenn were the top two scholars who made the largest contributions to this field. Keyword analysis showed that research hotspots changed from traumatic MO and clinical management of MO to the genetic etiology, pathogenesis, and treatment of FOP. This study can provide new insights into the research trends of MO and helps researchers grasp and determine future study directions more easily.

Jianpi Jiedu decoction suppresses colorectal cancer growth by inhibiting M2 polarization of TAMs through the tryptophan metabolism-AhR pathway.

BACKGROUND: Traditional Chinese medicine, JianpiJiedu decoction (JPJDF), has been utilized in colorectal cancer (CRC) treatment for over forty years. The potential of JPJDF to inhibit CRC through modulation of intestinal microbiota and their metabolites remains uncertain. AIMS: This study aims to further investigate the therapeutic mechanisms of JPJDF in CRC. METHODS: CAC mouse models were developed using azoxymethane (AOM) and dextran sulfate sodium (DSS). Intestinal tissues and contents underwent 16S rRNA gene sequencing and untargeted metabolomics analysis. Serum levels of IL-1ß and TNF-α were measured using ELISA. Immunohistochemistry was utilized to assess the expression of Ki67, ZO-1, Occludin, CD68, and CD206. Furthermore, western blotting was performed to evaluate the protein expression of AhR and NF-κB. RESULTS: JPJDF inhibited colorectal tumourigenesis in AOM/DSS treated mice, while also suppressing tumor cell proliferation and upregulating the expression of tight junction proteins. The results of 16S rRNA gene sequencing analysis revealed that JPJDF altered intestinal microbiota composition by increasing the abundance of beneficial bacteria. Additionally, JPJDF reduced tryptophan metabolites, effectively alleviating inflammation and significantly restoring intestinal barrier function in CAC mice. Molecular biology experiments confirmed that JPJDF suppressed the expression levels of AhR and M2-type tumor-associated macrophages, thereby promoting anti-tumor immunity and exerting inhibitory effects on CAC growth. CONCLUSION: JPJDF can regulate the tryptophan metabolism-AhR pathway by modulating the gut microbiota, reducing intestinal inflammation, improving intestinal barrier function, enhancing anti-tumor immunity, and effectively inhibiting CAC growth.

Primary cilia mediate skeletogenic BMP and Hedgehog signaling in heterotopic ossification.

Heterotopic ossification (HO), defined as the formation of extraskeletal bone in muscle and soft tissues, is a diverse pathological process caused by either genetic mutations or inciting trauma. Fibrodysplasia ossificans progressiva (FOP) is a genetic form of HO caused by mutations in the bone morphogenetic protein (BMP) type I receptor gene activin A receptor type 1 (ACVR1). These mutations make ACVR1 hypersensitive to BMP and responsive to activin A. Hedgehog (Hh) signaling also contributes to HO development. However, the exact pathophysiology of how skeletogenic cells contribute to endochondral ossification in FOP remains unknown. Here, we showed that the wild-type or FOP-mutant ACVR1 localized in the cilia of stem cells from human exfoliated deciduous teeth with key FOP signaling components, including activin A receptor type 2A/2B, SMAD family member 1/5, and FK506-binding protein 12kD. Cilia suppression by deletion of intraflagellar transport 88 or ADP ribosylation factor like GTPase 3 effectively inhibited pathological BMP and Hh signaling, subdued aberrant chondro-osteogenic differentiation in primary mouse or human FOP cells, and diminished in vivo extraskeletal ossification in Acvr1Q207D, Sox2-Cre; Acvr1R206H/+ FOP mice and in burn tenotomy-treated wild-type mice. Our results provide a rationale for early and localized suppression of cilia in affected tissues after injury as a therapeutic strategy against either genetic or acquired HO.

Mycorrhizal associations relate to stable convergence in plant-microbial competition for nitrogen absorption under high nitrogen conditions.

Nitrogen (N) immobilization (Nim, including microbial N assimilation) and plant N uptake (PNU) are the two most important pathways of N retention in soils. The ratio of Nim to PNU (hereafter Nim:PNU ratio) generally reflects the degree of N limitation for plant growth in terrestrial ecosystems. However, the key factors driving the pattern of Nim:PNU ratio across global ecosystems remain unclear. Here, using a global data set of 1018 observations from 184 studies, we examined the relative importance of mycorrhizal associations, climate, plant, and soil properties on the Nim:PNU ratio across terrestrial ecosystems. Our results show that mycorrhizal fungi type (arbuscular mycorrhizal (AM) or ectomycorrhizal (EM) fungi) in combination with soil inorganic N mainly explain the global variation in the Nim:PNU ratio in terrestrial ecosystems. In AM fungi-associated ecosystems, the relationship between Nim and PNU displays a weaker negative correlation (r = -.06, p < .001), whereas there is a stronger positive correlation (r = .25, p < .001) in EM fungi-associated ecosystems. Our meta-analysis thus suggests that the AM-associated plants display a weak interaction with soil microorganisms for N absorption, while EM-associated plants cooperate with soil microorganisms. Furthermore, we find that the Nim:PNU ratio for both AM- and EM-associated ecosystems gradually converge around a stable value (13.8 ± 0.5 for AM- and 12.1 ± 1.2 for EM-associated ecosystems) under high soil inorganic N conditions. Our findings highlight the dependence of plant-microbial interaction for N absorption on both plant mycorrhizal association and soil inorganic N, with the stable convergence of the Nim:PNU ratio under high soil N conditions.

Advances of the MAPK pathway in the treatment of spinal cord injury.

Spinal cord injury (SCI) represents a complex pathology within the central nervous system (CNS), leading to severe sensory and motor impairments. It activates various signaling pathways, notably the mitogen-activated protein kinase (MAPK) pathway. Present treatment approaches primarily focus on symptomatic relief, lacking efficacy in addressing the underlying pathophysiological mechanisms. Emerging research underscores the significance of the MAPK pathway in neuronal differentiation, growth, survival, axonal regeneration, and inflammatory responses post-SCI. Modulating this pathway post-injury has shown promise in attenuating inflammation, minimizing apoptosis, alleviating neuropathic pain, and fostering neural regeneration. Given its pivotal role, the MAPK pathway emerges as a potential therapeutic target in SCI management. This review synthesizes current knowledge on SCI pathology, delineates the MAPK pathway's characteristics, and explores its dual roles in SCI pathology and therapeutic interventions. Furthermore, it addresses the existing challenges in MAPK research in the context of SCI, proposing solutions to overcome these hurdles. Our aim is to offer a comprehensive reference for future research on the MAPK pathway and SCI, laying the groundwork for targeted therapeutic strategies.

A transition from arbuscular to ectomycorrhizal forests halts soil carbon sequestration during subtropical forest rewilding.

Ecological succession and restoration rapidly promote multiple dimensions of ecosystem functions and mitigate global climate change. However, the factors governing the limited capacity to sequester soil organic carbon (SOC) in old forests are poorly understood. Ecological theory predicts that plants and microorganisms jointly evolve into a more mutualistic relationship to accelerate detritus decomposition and nutrient regeneration in old than young forests, likely explaining the changes in C sinks across forest succession or rewilding. To test this hypothesis, we conducted a field experiment of root-mycorrhizal exclusion in successional subtropical forests to investigate plant-decomposer interactions and their effects on SOC sequestration. Our results showed that SOC accrual rate at the 0-10 cm soil layer was 1.26 mg g-1 yr-1 in early-successional arbuscular mycorrhizal (AM) forests, which was higher than that in the late-successional ectomycorrhizal (EcM) forests with non-significant change. A transition from early-successional AM to late-successional EcM forests increase fungal diversity, especially EcM fungi. In the late-successional forests, the presence of ectomycorrhizal hyphae promotes SOC decomposition and nutrient cycle by increasing soil nitrogen and phosphorus degrading enzyme activity as well as saprotrophic microbial richness. Across early- to late-successional forests, mycorrhizal priming effects on SOC decomposition explain a slow-down in the capacity of older forests to sequester soil C. Our findings suggest that a transition from AM to EcM forests supporting greater C decomposition can halt the capacity of forests to provide nature-based global climate change solutions.

Dual-source dual-energy CT and deep learning for equivocal lymph nodes on CT images for thyroid cancer.

OBJECTIVES: This study investigated the diagnostic performance of dual-energy computed tomography (CT) and deep learning for the preoperative classification of equivocal lymph nodes (LNs) on CT images in thyroid cancer patients. METHODS: In this prospective study, from October 2020 to March 2021, 375 patients with thyroid disease underwent thin-section dual-energy thyroid CT at a small field of view (FOV) and thyroid surgery. The data of 183 patients with 281 LNs were analyzed. The targeted LNs were negative or equivocal on small FOV CT images. Six deep-learning models were used to classify the LNs on conventional CT images. The performance of all models was compared with pathology reports. RESULTS: Of the 281 LNs, 65.5% had a short diameter of less than 4 mm. Multiple quantitative dual-energy CT parameters significantly differed between benign and malignant LNs. Multivariable logistic regression analyses showed that the best combination of parameters had an area under the curve (AUC) of 0.857, with excellent consistency and discrimination, and its diagnostic accuracy and sensitivity were 74.4% and 84.2%, respectively (p < 0.001). The visual geometry group 16 (VGG16) based model achieved the best accuracy (86%) and sensitivity (88%) in differentiating between benign and malignant LNs, with an AUC of 0.89. CONCLUSIONS: The VGG16 model based on small FOV CT images showed better diagnostic accuracy and sensitivity than the spectral parameter model. Our study presents a noninvasive and convenient imaging biomarker to predict malignant LNs without suspicious CT features in thyroid cancer patients. CLINICAL RELEVANCE STATEMENT: Our study presents a deep-learning-based model to predict malignant lymph nodes in thyroid cancer without suspicious features on conventional CT images, which shows better diagnostic accuracy and sensitivity than the regression model based on spectral parameters. KEY POINTS: Many cervical lymph nodes (LNs) do not express suspicious features on conventional computed tomography (CT). Dual-energy CT parameters can distinguish between benign and malignant LNs. Visual geometry group 16 model shows superior diagnostic accuracy and sensitivity for malignant LNs.

Recent advances in flexible memristors for advanced computing and sensing.

Conventional computing systems based on von Neumann architecture face challenges such as high power consumption and limited data processing capability. Improving device performance via scaling guided by Moore's Law becomes increasingly difficult. Emerging memristors can provide a promising solution for achieving high-performance computing systems with low power consumption. In particular, the development of flexible memristors is an important topic for wearable electronics, which can lead to intelligent systems in daily life with high computing capacity and efficiency. Here, recent advances in flexible memristors are reviewed, from operating mechanisms and typical materials to representative applications. Potential directions and challenges for future study in this area are also discussed.

Rational design of diblock copolymer enables efficient cytosolic protein delivery.

Polymer-mediated cytosolic protein delivery demonstrates a promising strategy for the development of protein therapeutics. Here, we propose a new designed diblock copolymer which realizes efficient cytosolic protein delivery both in vitro and in vivo. The polymer contains one protein-binding block composed of phenylboronic acid (PBA) and N-(3-dimethylaminopropyl) (DMAP) pendant units for protein binding and endosomal escape, respectively, followed by the response to ATP enriched in the cytosol which triggers the protein release. The other block is PEG designed to improve particle size control and circulation in vivo. By optimizing the block composition, sequence and length of the copolymer, the optimal one (BP20) was identified with the binding block containing 20 units of both PBA and DMAP, randomly distributed along the chain. When mixed with proteins, the BP20 forms stable nanoparticles and mediates efficient cytosolic delivery of a wide range of proteins including enzymes, toxic proteins and CRISPR/Cas9 ribonucleoproteins (RNP), to various cell lines. The PEG block, especially when further modified with folic acid (FA), enables tumor-targeted delivery of Saporin in vivo, which significantly suppresses the tumor growth. Our results shall inspire the design of novel polymeric vehicles with robust capability for cytosolic protein delivery, which holds great potential for both biological research and therapeutic applications.