Complementary Alu sequences mediate enhancer-promoter selectivity.

Enhancers determine spatiotemporal gene expression programs by engaging with long-range promoters1-4. However, it remains unknown how enhancers find their cognate promoters. We recently developed a RNA in situ conformation sequencing technology to identify enhancer-promoter connectivity using pairwise interacting enhancer RNAs and promoter-derived noncoding RNAs5,6. Here we apply this technology to generate high-confidence enhancer-promoter RNA interaction maps in six additional cell lines. Using these maps, we discover that 37.9% of the enhancer-promoter RNA interaction sites are overlapped with Alu sequences. These pairwise interacting Alu and non-Alu RNA sequences tend to be complementary and potentially form duplexes. Knockout of Alu elements compromises enhancer-promoter looping, whereas Alu insertion or CRISPR-dCasRx-mediated Alu tethering to unregulated promoter RNAs can create new loops to homologous enhancers. Mapping 535,404 noncoding risk variants back to the enhancer-promoter RNA interaction maps enabled us to construct variant-to-function maps for interpreting their molecular functions, including 15,318 deletions or insertions in 11,677 Alu elements that affect 6,497 protein-coding genes. We further demonstrate that polymorphic Alu insertion at the PTK2 enhancer can promote tumorigenesis. Our study uncovers a principle for determining enhancer-promoter pairing specificity and provides a framework to link noncoding risk variants to their molecular functions.

RIC-seq for global in situ profiling of RNA-RNA spatial interactions.

Highly structured RNA molecules usually interact with each other, and associate with various RNA-binding proteins, to regulate critical biological processes. However, RNA structures and interactions in intact cells remain largely unknown. Here, by coupling proximity ligation mediated by RNA-binding proteins with deep sequencing, we report an RNA in situ conformation sequencing (RIC-seq) technology for the global profiling of intra- and intermolecular RNA-RNA interactions. This technique not only recapitulates known RNA secondary structures and tertiary interactions, but also facilitates the generation of three-dimensional (3D) interaction maps of RNA in human cells. Using these maps, we identify noncoding RNA targets globally, and discern RNA topological domains and trans-interacting hubs. We reveal that the functional connectivity of enhancers and promoters can be assigned using their pairwise-interacting RNAs. Furthermore, we show that CCAT1-5L-a super-enhancer hub RNA-interacts with the RNA-binding protein hnRNPK, as well as RNA derived from the MYC promoter and enhancer, to boost MYC transcription by modulating chromatin looping. Our study demonstrates the power and applicability of RIC-seq in discovering the 3D structures, interactions and regulatory roles of RNA.

Changes of brain functional network in Alzheimer's disease and frontotemporal dementia: a graph-theoretic analysis.

BACKGROUND: Alzheimer's disease (AD) and frontotemporal dementia (FTD) are the two most common neurodegenerative dementias, presenting with similar clinical features that challenge accurate diagnosis. Despite extensive research, the underlying pathophysiological mechanisms remain unclear, and effective treatments are limited. This study aims to investigate the alterations in brain network connectivity associated with AD and FTD to enhance our understanding of their pathophysiology and establish a scientific foundation for their diagnosis and treatment. METHODS: We analyzed preprocessed electroencephalogram (EEG) data from the OpenNeuro public dataset, comprising 36 patients with AD, 23 patients with FTD, and 29 healthy controls (HC). Participants were in a resting state with eyes closed. We estimated the average functional connectivity using the Phase Lag Index (PLI) for lower frequencies (delta and theta) and the Amplitude Envelope Correlation with leakage correction (AEC-c) for higher frequencies (alpha, beta, and gamma). Graph theory was applied to calculate topological parameters, including mean node degree, clustering coefficient, characteristic path length, global and local efficiency. A permutation test was then utilized to assess changes in brain network connectivity in AD and FTD based on these parameters. RESULTS: Both AD and FTD patients showed increased mean PLI values in the theta frequency band, along with increases in average node degree, clustering coefficient, global efficiency, and local efficiency. Conversely, mean AEC-c values in the alpha frequency band were notably diminished, which was accompanied by decreases average node degree, clustering coefficient, global efficiency, and local efficiency. Furthermore, AD patients in the occipital region showed an increase in theta band node degree and decreased alpha band clustering coefficient and local efficiency, a pattern not observed in FTD. CONCLUSIONS: Our findings reveal distinct abnormalities in the functional network topology and connectivity in AD and FTD, which may contribute to a better understanding of the pathophysiological mechanisms of these diseases. Specifically, patients with AD demonstrated a more widespread change in functional connectivity, while those with FTD retained connectivity in the occipital lobe. These observations could provide valuable insights for developing electrophysiological markers to differentiate between the two diseases.

The growth mechanism of PtS2 single crystal.

PtS2, a member of the group 10 transition metal dichalcogenides (TMDs), has received extensive attention because of its excellent electrical properties and air stability. However, there are few reports on the preparation of single-crystal PtS2 in the literature, and the growth mechanism of single crystal PtS2 is not well elucidated. In this work, we proposed a method of preparation that combines magnetron sputtering and chemical vapor transport to obtain monocrystalline PtS2 on a SiO2/Si substrate. By controlling the growth temperature and time, we have synthesized a single crystalline PtS2 of hexagonal shape and size of 1-2 µm on a silicon substrate. Combining the molecular dynamics simulation, the growth mechanism of single crystal PtS2 was investigated both experimentally and theoretically. The synthesis method has a short production cycle and low cost, which opens the door for the fabrication of other TMDs single crystals.

Synergistic Effect of Ni/Ni(OH)2 Core-Shell Catalyst Boosts Tandem Nitrate Reduction for Ampere-Level Ammonia Production.

Electrocatalytic reduction of nitrate to ammonia provides a green alternate to the Haber-Bosch method, yet it suffers from sluggish kinetics and a low yield rate. The nitrate reduction follows a tandem reaction of nitrate reduction to nitrite and subsequent nitrite hydrogenation to generate ammonia, and the ammonia Faraday efficiency (FE) is limited by the competitive hydrogen evolution reaction. Herein, we design a heterostructure catalyst to remedy the above issues, which consists of Ni nanosphere core and Ni(OH)2 nanosheet shell (Ni/Ni(OH)2). In situ Raman spectroscopy reveals Ni and Ni(OH)2 are interconvertible according to the applied potential, facilitating the cascade nitrate reduction synergistically. Consequently, it attains superior electrocatalytic nitrate reduction performance with an ammonia FE of 98.50 % and a current density of 0.934 A cm-2 at -0.476 V versus reversible hydrogen electrode, and exhibits an average ammonia yield rate of 84.74 mg h-1 cm-2 during the 102-hour stability test, which is highly superior to the reported catalysts tested under similar conditions. Density functional theory calculations corroborate the synergistic effect of Ni and Ni(OH)2 in the tandem reaction of nitrate reduction. Moreover, the Ni/Ni(OH)2 catalyst also possesses good capability for methanol oxidation and thus is used to establish a system coupling with nitrate reduction.

Human γδ T cells induce CD8+ T cell antitumor responses via antigen-presenting effect through HSP90-MyD88-mediated activation of JNK.

Human Vγ9Vδ2 T cells have attracted considerable attention as novel alternative antigen-presenting cells (APCs) with the potential to replace dendritic cells in antitumor immunotherapy owing to their high proliferative capacity and low cost. However, the utility of γδ T cells as APCs to induce CD8+ T cell-mediated antitumor immune response, as well as the mechanism by which they perform APC functions, remains unexplored. In this study, we found that activated Vγ9Vδ2 T cells were capable of inducing robust CD8+ T cell responses in osteosarcoma cells. Activated γδ T cells also effectively suppressed osteosarcoma growth by priming CD8+ T cells in xenograft animal models. Mechanistically, we further revealed that activated γδ T cells exhibited increased HSP90 production, which fed back to upregulate MyD88, followed by JNK activation and a subsequent improvement in CCL5 secretion, leading to enhanced CD8+ T cell cross-priming. Thus, our study suggests that Vγ9Vδ2 T cells represent a promising alternative APC for the development of γδ T cell-based tumor immunotherapy.

Activated FeS2 @NiS2 Core-Shell Structure Boosting Cascade Reaction for Superior Electrocatalytic Oxygen Evolution.

Unlike single-step reactions, multi-step reactions can be greatly facilitated only if all the intermediate reactions can be catalyzed simultaneously and progressively. Herein, the theoretical analysis and experiments to illustrate the superiority of the cascade oxygen evolution reaction (OER) are conducted. As different OER intermediate reactions demand Fex Ni1-x OOH with altered Fe/Ni ratios, gradient Fe-doped NiOOH can be an ideal electrocatalyst for the efficient cascade OER in line. Fine controlling of the nucleation sequence of iron and nickel sulfides leads to a FeS2 @NiS2 core-shell structure. The activated outward diffusion of Fe dopants results in the gradient Fe/Ni ratios in the Fex Ni1-x OOH shell, where a cascade OER can happen. Electrochemical tests suggest that the FeS2 @NiS2 only needs an overpotential of 237 mV to reach the current density of 10 mA cm-2 , with fast reaction kinetics and good stability.

CTRP1: A novel player in cardiovascular and metabolic diseases.

Cardiovascular diseases (CVDs) are a series of diseases induced by inflammation and lipid metabolism disorders, among others. Metabolic diseases can cause inflammation and abnormal lipid metabolism. C1q/TNF-related proteins 1 (CTRP1) is a paralog of adiponectin that belongs to the CTRP subfamily. CTRP1 is expressed and secreted in adipocytes, macrophages, cardiomyocytes, and other cells. It promotes lipid and glucose metabolism but has bidirectional effects on the regulation of inflammation. Inflammation can also inversely stimulate CTRP1 production. A vicious circle may exist between the two. This article introduces CTRP1 from the structure, expression, and different roles of CTRP1 in CVDs and metabolic diseases, to summarize the role of CTRP1 pleiotropy. Moreover, the proteins which may interact with CTRP1 are predicted through GeneCards and STRING, speculating their effects, to provide new ideas for the study of CTRP1.

Association of Sarcopenia With Mortality in Patients With Chronic Limb-Threatening Ischemia Undergoing Endovascular Revascularization.

INTRODUCTION: Chronic limb-threatening ischemia (CLTI) is the most severe form of peripheral artery disease and leads high mortality. Sarcopenia, characterized by the loss of muscle mass or poor muscle quality, is associated with adverse clinical outcomes. This study aimed to investigate the association between sarcopenia and the long-term outcomes in patients with CLTI after endovascular revascularization. METHODS: We retrospectively reviewed the medical records of all patients with CLTI who underwent endovascular revascularization between January 2015, and December 2021. The skeletal muscle area was calculated at the third lumbar vertebra from computed tomography images using the manual trace method and normalized to patient height. Sarcopenia was defined as a third lumbar skeletal muscle index of <40.8 cm2/m2 in males and <34.9 cm2/m2 in females. The Kaplan-Meier and Cox proportional hazards regression analyses were used for survival analysis and to evaluate the association between sarcopenia and mortality. RESULTS: A total of 137 patients (90 men; mean age 71.7 ± 9.6 y) were enrolled for the study, of whom 56 (40.8%) had sarcopenia. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 71.2%. The sarcopenic group had a significantly worse 3-year overall survival rate than the nonsarcopenic group (55.3% versus 78.6%, P = 0.001). Multivariate Cox proportional hazard regression analyses revealed that sarcopenia (hazard ratio, 2.262; 95% confidence interval, 1.132-4.518; P = 0.021) and dialysis (hazard ratio, 3.021; 95% confidence interval, 1.337-6.823; P = 0.008) were independently associated with increased risk of all-cause mortality, whereas technical success had significantly opposing correlation with mortality. (hazard ratio, 0.400, 95% confidence interval, 0.194-0.826, P = 0.013). CONCLUSIONS: Sarcopenia can be highly prevalent in patients with CLTI who undergo endovascular revascularization, and is independently associated with long-term mortality. These results may help risk stratification to assist in personalized assessment and clinical decision-making.

Computational simulation-driven discovery of novel zeolite-like carbon materials as seawater desalination membranes.

Freshwater is a scarce and vulnerable resource that has never encountered such an extensive focus on a nearly worldwide scale as it does today. Recently, it has been found that desalination powered by two-dimensional (2D) carbon materials as separation membranes has significantly reduced the operational costs and complexity but presents heavy requirements for the structural stability and separation properties of the membrane materials. Here, we combined carbon materials with promising adsorption properties and zeolites characterized by a regular pore structure to obtain a zeolite-like structured carbon membrane Zeo-C and investigated the suitability of the Zeo-C membrane for seawater desalination based on the computational-simulation-driven approach. The results of molecular dynamics (MD) simulations and density functional theory (DFT) calculations revealed that the periodic pore distribution conferred favorable structural stability and mechanical strength to the Zeo-C desalination membrane. The rejection rate of Na+ and Cl- is ensured at 100% under a pressure of 40-70 MPa, and that of Na+ could reach 97.85% even though the pressure increases to 80 MPa, exhibiting superior desalination properties. The porous nature of the zeolite-like structure and the low free energy potential barrier are conducive for reliable adsorption and homogeneous diffusion of salt ions, which facilitates the acquisition of desirable water molecule permeability and salt ion selectivity. In particular, the interlinked delocalized π-network imparts inherent metallicity to Zeo-C for self-cleaning in response to electrical stimulation, thereby extending the lifetime of the desalination membrane. These studies have greatly encouraged theoretical innovations and serve as a guiding reference for desalination materials.

Electron-level insight into efficient synergistic oxygen evolution catalysis at multimetallic sites in PtNiFeCoCu high-entropy alloys.

The exploration of high-quality and efficient electrocatalysts is crucial for the advancement of clean energy utilization and the development of energy conversion technologies. Recently, high-entropy alloys (HEA) have been actively explored as viable catalysts for water electrolysis due to their unique performance such as wide scope for compositional adjustments, excellent catalytic activity, and outstanding stability. However, the mechanism of synergistic oxygen evolution by HEA electrocatalysts at multiple sites has not been systematically and clearly demystified. Herein, in this paper, Pt is combined with inexpensive metals Ni, Cu, Fe, and Co to form a stable HEA structure. The synergistic catalytic mechanism of the PtNiFeCoCu HEA in the oxygen evolution reaction (OER) has been investigated, and the structure has been demonstrated to exhibit excellent hydrogen evolution reaction (HER) activity. The results suggest that the PtNiFeCoCu HEA catalyst achieved a lower overpotential of 0.44 V in the acidic OER, demonstrating that the PtNiFeCoCu HEA is a bifunctional electrocatalyst. In addition, oxygen intermediates are synergistically adsorbed on the surface of high-entropy alloys through multimetallic sites, which breaks the limitation of limited active sites. Further calculations indicated that the favorable OER activity of the catalyst originated from the strong associative coupling of the d orbitals of the synergistic metal sites to the 2p orbitals of the oxygen intermediates with enhanced synergistic effects. This work further elucidates the multisite synergistic catalysis of the PtNiFeCoCu HEA, providing a unique perspective to uncover the source of the high catalytic performance of HEA electrocatalysts.

Surface/interfacial transport through pores control desalination mechanisms in 2D carbon-based membranes.

The shortage of freshwater is a critical concern for contemporary society, and reverse osmosis desalination technology has gathered considerable attention as a potential solution to this problem. It has been recognized that the desalination process involving water flow through angstrom-sized pores has tremendous potential. However, it is challenging to obtain angstrom-sized pore structures with internal mass transfer and surface/interface properties matching the application conditions. Herein, a two-dimensional (2D) zeolite-like carbon structure (Carzeo-ANG) was constructed with unique angstrom-sized pores in the zeolite structure; then, the surface/interfacial transport behavior and percolation effect of the Carzeo-ANG desalination membrane were evaluated by density functional theory (DFT) calculations and classical molecular dynamics. The first-principles calculations in density functional theory were implemented through the Vienna ab initio simulation package (VASP), which is a commercial package for the simulation of carbon-based materials. The results show that Carzeo-ANG is periodically distributed with angstrom-sized pores (effective diameter = 5.4 Å) of dodecacyclic carbon rings, which ensure structural stability while maintaining sufficient mechanical strength. The remarkable salt-ion adsorption properties and mass transfer activity combined with the reasonable density distribution and free energy barrier for water molecules endow the membrane with superior desalination ability. At the pressure of 80 MPa, the rejection efficiency of Cl- and Na+ were 100% and 96.25%, and the membrane could achieve a water flux of 132.71 L cm-2 day-1 MPa-1. Moreover, the interconnected electronic structure of Carzeo-ANG imparts a self-cleaning effect.

New insights into phase transition behavior and electrochemistry corrosion of three-dimensional biphenylene.

It is estimated that the annual cost of corrosion in most countries accounts for 3-4% of gross domestic product, far exceeding the losses caused by natural disasters, prompting scientists to continuously search for high-performance anti-corrosion materials. Among these high-performance materials, two-dimensional carbon materials represented by graphene have received widespread attention due to their excellent chemical stability and anti-permeability. However, some studies have found that the poor ability of graphene to bind to the interface and the electrical coupling caused by metallicity make it possible to protect copper from corrosion only for a short period of time. To circumvent these issues, through phase behavior research, interface binding property simulation and corrosion mechanism exploration, we propose a more promising anti-corrosive three-dimensional (3D) biphenylene diamond-like carbon membrane (BP-DLC). The kinetic study results show that due to the Gibbs free energy of biphenylene structures below three layers being lower than 0, few-layer biphenylene can spontaneously generate phase transitions of limited size, forming a biphenylene diamond-like membrane and exhibiting superior mechanical properties and a certain degree of flexibility. Mechanical and electronic performance results further show that there is a strong bonding effect between BP-DLC and the metal surface, which further enhances the bistate heterostructure and prolongs the coating life of BP-DLC materials. Compared with pure graphene and Cu substrates, BP-DLC membranes exhibit stronger corrosion resistance by reducing porosity, increasing charge transfer and hindering the diffusion of corrosion ions to the substrate. This study provides a new strategy for constructing corrosion-resistant materials by designing long-term stable and highly corrosion-resistant diamond-like membranes.

Thermal and electrical transport properties of two-dimensional Dirac graphenylene: a first-principles study.

The development of high performance two-dimensional thermoelectric (TE) materials is crucial for enhancing the conversion of waste heat into electricity and for achieving the transition to new energy. In recent years, two-dimensional Dirac materials with high carrier mobility and non-trivial topological properties have been expected to extend the application of carbon-based materials in the TE field. However, research on the TE properties of two-dimensional Dirac materials is still scarce, and the relevant physical mechanisms that affect the TE figure of merit of the materials are still unclear. Therefore, we carefully selected a typical and experimentally synthesized Dirac structure, graphenylene, and systematically studied its thermal transport and electrical transport properties using density functional theory (DFT) and Boltzmann transport theory. The results show that the ZT value of graphenylene exhibits an extremely significant anisotropy. There is a significant discrepancy in the figure of merit (ZT) values of n-type and p-type systems at the optimum doping concentration, i.e., the ZT value of the n-type system (0.49) is one order of magnitude greater than that of the p-type system (0.06). Graphenylene exhibits excellent electronic performance due to its unique electronic band structure and has an extremely high conductivity (for the n-type system, electrical conductivity at room temperature is 109 S m-1). Interestingly, graphenylene has an unusually higher ZT at low temperature (0.5 at 300 K) than at high temperature (0.3 at 800 K) for n-type doping along the x-axis, contrary to the conventional view that higher ZT values exist in the high temperature range. This work provides a deep insight into the TE properties of two-dimensional Dirac carbon materials and offers new perspectives for enhancing the TE performance and application of carbon-based nanomaterials.

Insight into the Fe atom-FeS cluster synergistic catalysis mechanism for the oxygen evolution reaction in NiS2-based electrocatalysts.

The development of highly active oxygen evolution reaction (OER) catalysts with fast kinetics is crucial for the advancement of clean energy and fuel conversion to achieve a sustainable energy future. Recently, the synergistic effect of single-atom doping and multicomponent clusters has been demonstrated to significantly improve the catalytic activity of materials. However, such synergistic effects involving multi-electron and proton transfer processes are quite complex and many crucial mechanistic details need be well comprehended. We ingeniously propose a catalyst, (Fed-FeSc)@NiS2 (d stands for doping and c stands for clustering), with Fe and FeS acting synergistically on a NiS2 substrate. Specifically, fully dynamic monitoring of multiple active sites at the (Fed-FeSc)@NiS2 interface using metadynamics is innovatively performed. The results show that the rate determining step value at the overpotential of 1.23 V for the synergistic (Fed-FeSc)@NiS2 is 1.55 V, decreased by 6.67% and 35.29% compared to those of the independently acting single-atom doping and multi-clusters. The unique synergistic structure dramatically increases the d-band centre of the Fe site (-1.45 eV), endowing (Fed-FeSc)@NiS2 with more activity than conventional commercial Ir-C catalysts. This study provides insights into the synergistic effects of single-atom doping and multi-component clusters, leading to exploratory inspiration for the design of highly efficient OER catalysts.

Differences in intestinal motility during different sleep stages based on long-term bowel sounds.

BACKGROUND AND OBJECTIVES: This study focused on changes in intestinal motility during different sleep stages based on long-term bowel sounds. METHODS: A modified higher order statistics algorithm was devised to identify the effective bowel sound segments. Next, characteristic values (CVs) were extracted from each bowel sound segment, which included 4 time-domain, 4 frequency-domain and 2 nonlinear CVs. The statistical analysis of these CVs corresponding to the different sleep stages could be used to evaluate the changes in intestinal motility during sleep. RESULTS: A total of 6865.81 min of data were recorded from 14 participants, including both polysomnographic data and bowel sound data which were recorded simultaneously from each participant. The average accuracy, sensitivity and specificity of the modified higher order statistics detector were 96.46 ± 2.60%, 97.24 ± 2.99% and 94.13 ± 4.37%. In addition, 217088 segments of effective bowel sound corresponding to different sleep stages were identified using the modified detector. Most of the CVs were statistically different during different sleep stages ([Formula: see text]). Furthermore, the bowel sounds were low in frequency based on frequency-domain CVs, high in energy based on time-domain CVs and low in complexity base on nonlinear CVs during deep sleep, which was consistent with the state of the EEG signals during deep sleep. CONCLUSIONS: The intestinal motility varies by different sleep stages based on long-term bowel sounds using the modified higher order statistics detector. The study indicates that the long-term bowel sounds can well reflect intestinal motility during sleep. This study also demonstrates that it is technically feasible to simultaneously record intestinal motility and sleep state throughout the night. This offers great potential for future studies investigating intestinal motility during sleep and related clinical applications.

3D-printed hydrogel particles containing PRP laden with TDSCs promote tendon repair in a rat model of tendinopathy.

Long-term chronic inflammation after Achilles tendon injury is critical for tendinopathy. Platelet-rich plasma (PRP) injection, which is a common method for treating tendinopathy, has positive effects on tendon repair. In addition, tendon-derived stem cells (TDSCs), which are stem cells located in tendons, play a major role in maintaining tissue homeostasis and postinjury repair. In this study, injectable gelatine methacryloyl (GelMA) microparticles containing PRP laden with TDSCs (PRP-TDSC-GM) were prepared by a projection-based 3D bioprinting technique. Our results showed that PRP-TDSC-GM could promote tendon differentiation in TDSCs and reduce the inflammatory response by downregulating the PI3K-AKT pathway, thus promoting the structural and functional repair of tendons in vivo.

Valuing the plant species diversity of permanent grasslands: From the perspective of herders.

Conserving plant species diversity is crucial to the sustainable development of human beings. Nevertheless, the trends toward declining species numbers and homogenization of species distributions have become increasingly evident. The monetary value of species diversity can make stakeholders put more serious attentions on the protection of species diversity, but which is difficult to evaluate. This paper combined survey data and ecological data obtained through plot sampling and geographic information system methods, to assess the value of plant species diversity in permanent grasslands for local herders who are the direct users of grasslands, and whose livelihoods and well-beings are tightly related with the ecosystem of grasslands. Based on the life satisfaction approach, we found that the monetary value of one plant species for each herder household is equivalent to 9.8% of the annual household income on average, which increases to 15.9% when the level of species evenness is higher. The results of a heterogeneity analysis revealed that the value of plant species diversity varies significantly among different groups of households. Our research introduced a new method to quantify the value of species diversity for stakeholders. The estimation of monetary value of plant species diversity will have far-reaching influence on stakeholders and policymakers involved in protecting species diversity of permanent grasslands.

Vascular Derived ECM Improves Therapeutic Index of BMP-2 and Drives Vascularized Bone Regeneration.

Vascularized osteogenesis is essential for successful bone regeneration, yet its realization during large size bone defect healing remains challenging due to the difficulty to couple multiple biological processes. Herein, harnessing the intrinsic angiogenic potential of vascular derived extracellular matrix (vECM) and its specific affinity to growth factors, a vECM/GelMA based hybrid hydrogel delivery system is constructed to achieve optimized bone morphogenetic protein-2 (BMP-2) therapeutic index and provide intrinsic angiogenic induction during bone healing. The incorporation of vECM not only effectively regulates BMP-2 kinetics to match the bone healing timeframe, but also promotes angiogenesis both in vitro and in vivo. In vivo results also show that vECM-mediated BMP-2 release remarkably enhances vascularized bone formation for critical size bone defects. In particular, blood vessel ingrowth stained with CD31 marker in the defect area is substantially encouraged over the course of healing, suggesting incorporation of vECM served roles in both angiogenesis and osteogenesis. Thus, the authors' study exemplifies that affinity of growth factor towards ECM may be a promising strategy to be leveraged to develop sophisticated delivery systems endowed with desirable properties for regenerative medicine applications.