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The treatment of full-thickness skin injuries complicated by severe infection is hampered by the lack of comprehensive solutions that can regulate the various stages of wound healing. Consequently, there is an urgent need for a multifunctional dressing capable of multi-level regulation. In this study, we propose a novel solution by covalently integrating ε-poly-l-lysine-grafted gallic acid (EG) and in situ bioreduced silver nanoparticles (AgNPs) onto nano-hydroxyapatite (nHAP), thereby developing a multi-layered, multifunctional nanoplatform (nHEA). Cell experiments have shown that, compared to nHAP and nHAP loaded only with EG (nHEG), the addition of AgNPs to nHEA confers excellent antibacterial properties while maintaining optimal biocompatibility. The incorporation of EG onto nHEG and nHEA imparts antioxidation, anti-inflammatory, and pro-angiogenic functions, and the release of Ca2+ and EG further enhances fibroblast migration and collagen secretion. In a rat model of full-thickness skin injury with severe infection, nHEA demonstrates remarkable antibacterial and anti-inflammatory effects, along with promoting collagen remodeling and regeneration. Together, both cell experiments and animal studies confirm the significant potential of this innovative multifunctional nanoplatform in the treatment of full-thickness skin injuries with severe infection. Treating infected full-thickness skin injuries poses a longstanding challenge due to the lack of comprehensive solutions that can regulate different stages of wound healing. This study introduces a novel multifunctional nanoplatform, nHEA, developed by covalently integrating ε-poly-l-lysine grafted with gallic acid (EG) and in situ bioreduced AgNPs onto nano-hydroxyapatite (nHAP). Cell experiments reveal that the integration of AgNPs enhances nHEA's antibacterial performance while maintaining optimal biocompatibility. The inclusion of EG bestows antioxidant, inflammation-regulating, and angiogenetic properties upon nHEA, and the release of Ca2+ and EG stimulates the migration and collagen secretion of fibroblast cells. Consequently, nHEA exhibits superior antibacterial and inflammation-regulating efficacy, and stimulates collagen remodeling and regeneration in vivo , making it a promising treatment for severely infected skin injuries. [Display omitted] [ABSTRACT FROM AUTHOR]

• Isolation and characterization of MOEVLPs. • Verification of anti-PMOP effect of MOEVLPs. • Determination of anti-PMOP mechanism of MOEVLPs. • Validation of MOEVLPs' potential use as a novel, natural anti-PMOP drug. • Exploration of strategies for the study of plant-derived extracellular vesicles. Postmenopausal osteoporosis (PMOP) is a systemic bone disease characterized by low bone mass and microstructural damage. Morinda Officinalis (MO) contains various components with anti-PMOP activities. Morinda Officinalis -derived extracellular vesicle-like particles (MOEVLPs) are new active components isolated from MO, and no relevant studies have investigated their anti-osteoporosis effect and mechanism. To investigate the alleviating effect of MOEVLPs on PMOP and the underlying mechanism. Differential centrifugation and ultracentrifugation were used to isolate MOEVLPs from MO. Transmission electron microscopy (TEM), flow nano analyzer, sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), agarose gel electrophoresis, and thin-layer chromatography were employed to characterize MOEVLPs. PMOP mouse models were utilized to examine the anti-PMOP effect of MOEVLPs. H&E and immunohistochemical staining were used for drug safety and osteogenic effect assessment. Mouse embryo osteoblast precursor cells (MC3T3-E1) were used in vitro experiments. CCK-8 kit, alizarin red staining, proteomic, bioinformatic analyses, and western blot were used to explore the mechanism of MOEVLPs. In this study, MOEVLPs from MO were successfully isolated and characterized. Animal experiments demonstrated that MOEVLPs exhibited specific femur targeting, were non-toxic to the heart, liver, spleen, lung, kidney, and aorta, and possessed anti-PMOP properties. The ability of MOEVLPs to strengthen bone formation was better than that of alendronate. In vitro experiments, results revealed that MOEVLPs did not significantly enhance osteogenic differentiation in MC3T3-E1 cells. Instead, MOEVLPs promoted the proliferation of MC3T3-E1 cells. Proteomic and bioinformatic analyses suggested that the proliferative effect of MOEVLPs was closely associated with the mitogen-activated protein kinase (MAPK) signaling pathway, particularly the altered expression of cAMP response element-binding protein (CREB) and ribosomal S6 kinase 1 (RSK1). Western blot results further confirmed these findings. Our studies successfully isolated high-quality MOEVLPs and demonstrated that MOEVLPs can alleviate PMOP by promoting osteoblast proliferation through the MAPK pathway. MOEVLPs have the potential to become a novel and natural anti-PMOP drug. [Display omitted] [ABSTRACT FROM AUTHOR]

• Oxymatrine improves motor performance and delays disease progression in ALS mice. • Oxymatrine attenuates motor neuron loss, microgliosis, and astrogliosis in ALS mice. • Oxymatrine regulates the gene expression of inflammation-related factors in ALS mice. • Oxymatrine modulates the gene expression of insulin signaling molecules in ALS mice. Amyotrophic lateral sclerosis (ALS) is one of the leading causes of death associated with neurodegenerative diseases worldwide, and the progression of the disease is characteristically accompanied by severe neuroinflammation. Neuroprotective effects of oxymatrine (OMT) were shown to be due to reduced neuroinflammation in the mouse models of Alzheimer's disease and Parkinson's disease. The present study investigated whether OMT has a therapeutic potential in transgenic SOD1-G93A (TgSOD1-G93A) mice. Daily OMT treatment started at the age of 55 days until the end stage of the disease. Body weight and rotarod motor performance were assessed every 3 days starting from 70 days of age. Footprints were recorded to measure the stride length 40 days and 60 days after the initiation of the treatment. Some animals were sacrificed at the age of 115 days, and the lumbar spinal cord was harvested for immunofluorescence and quantitative real-time polymerase chain reaction (qRT-PCR) to evaluate the neuroinflammatory responses. The results indicated that treatment with OMT delayed body weight loss, improved motor performance, and prolonged the survival of SOD1-G93A mice. Mechanistically, OMT treatment enhanced motor neuronal survival and alleviated the activation of microglia and astrocytes compared with those in the vehicle-treated group. Furthermore, the expression of the proinflammatory mediators was downregulated, and the expression of the anti-inflammatory factors was upregulated in the OMT-treated group compared with those in the vehicle-treated group (P < 0.05). Thus, the treatment with OMT had neuroprotective effects, promoting neuronal survival and extending the lifetime of SOD1-G93A mice by suppressing neuroinflammation. [ABSTRACT FROM AUTHOR]

With the aim of developing a fast algorithm for high-quality MRI reconstruction from undersampled k-space data, we propose a novel deep neural Network, which is inspired by Iterative Shrinkage Thresholding Algorithm with Data consistency (NISTAD). NISTAD consists of three consecutive blocks: an encoding block, which models the flow graph of ISTA, a classical iteration-based compressed sensing magnetic resonance imaging (CS-MRI) method; a decoding block, which recovers the image from sparse representation; a data consistency block, which adaptively enforces consistency with the acquired raw data according to learned noise level. The ISTA method is thereby mapped to an end-to-end deep neural network, which greatly reduces the reconstruction time and simplifies the tuning of hyper-parameters, compared to conventional model-based CS-MRI methods. On the other hand, compared to general deep learning-based MRI reconstruction methods, the proposed method uses a simpler network architecture with fewer parameters. NISTAD has been validated on retrospectively undersampled diencephalon standard challenge data using different acceleration factors, and compared with DAGAN and Cascade CNN, two state-of-the-art deep neural network-based methods which outperformed many other state-of-the-art model-based and deep learning-based methods. Experimental results demonstrated that NISTAD reconstruction achieved comparable image quality with DAGAN and Cascade CNN reconstruction in terms of both PSNR and SSIM metrics, and subjective assessment, though with a simpler network structure. [ABSTRACT FROM AUTHOR]

• Notch signaling pathway plays a pivotal role in the pathogenesis of ALS mice. • Notch activation occurs mainly in astrocytes in spinal cord of ALS mice. • Jagged1-Notch signaling pathway is principally mediated by microglia. • DLL4-Notch signaling pathway is mediated by astrocytes and oligodendrocytes. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by motor neuron loss and gliosis in the spinal cord, brain stem and cortex. The Notch signaling pathway has been reported to be dysfunctional in neurodegenerative diseases, including ALS. However, the exact mechanism is still unclear. Here, we detected Notch signaling activation in proliferating glial cells, Notch inactivation in motor neurons in the spinal cord of the SOD1-G93A model, and dramatic changes of cellular relocalization of Notch pathway signaling molecules, including activated Notch intracellular domain (NICD), Notch ligands (Jagged1 and DLL4) and the target gene Hes1. We found that Notch activation was universal in proliferating astrocytes and that the Notch ligand Jagged1 was uniquely upregulated in proliferating microglia, while DLL4 expression was increased in both activated astrocytes and degenerating oligodendrocytes. Our results indicate that microglia may play an important role in the intercellular receptor-ligand interaction of the Notch signaling pathway and contribute to the pathogenesis of motor neuron loss in ALS mice. Further experiments are required to clarify the exact mechanism responsible for Notch dysfunction in ALS. [ABSTRACT FROM AUTHOR]

Various sparse transform models have been explored for compressed sensing-based dynamic cardiac MRI reconstruction from vastly under-sampled k-space data. Recently emerged low rank tensor model using Tucker decomposition could be viewed as a special form of sparse model, where the core tensor, which is obtained using high-order singular value decomposition, is sparse in the sense that only a few elements have dominantly large magnitude. However, local details tend to be over-smoothed when the entire image is conventionally modeled as a global tensor. Moreover, low rankness is sensitive to motion as spatiotemporal correlation is corrupted by spatial misalignment between temporal frames. To overcome these limitations, this paper presents a novel motion aligned locally low rank tensor (MALLRT) model for dynamic MRI reconstruction. In MALLRT, low rank constraint is enforced on image patch-based local tensors, which correspond to overlapping blocks extracted from the reconstructed high-dimensional image after group-wise inter-frame motion registration. For solving the proposed model, this paper presents an efficient optimization algorithm by using variable splitting and alternating direction method of multipliers (ADMM). MALLRT demonstrated promising performance as validated on one cardiac perfusion MRI dataset and two cardiac cine MRI datasets using retrospective under-sampling with various acceleration factors, as well as one prospectively under-sampled cardiac perfusion MRI dataset. Compared to four state-of-the-art methods, MALLRT achieved substantially better image reconstruction quality in terms of both signal to error ratio (SER) and structural similarity index (SSIM) metrics, and visual perception in preserving spatial details and capturing temporal variations. [ABSTRACT FROM AUTHOR]

Hydrogels, which provide three-dimensional (3D) niches for encapsulating bone marrow mesenchymal stem cells (BMSCs), are becoming a promising tissue engineering solution for chondrogenic differentiation of BMSCs. However, it remains a challenge to design a hydrogel material for effective chondrogenesis of BMSCs because of the complexity of cartilage ECM and cell–matrix interactions. Thus far, various studies have shown the physical–chemical cues of hydrogel materials to impact BMSCs chondrogenesis, but the design of the 3D network microstructure of the hydrogel to induce BMSCs chondrogenesis is still far from optimized. In this study, we successfully prepared two types of collagen hydrogels, namely, the fibrous network and porous network, with the same chemical composition and similar mechanical strength but with two distinct network microstructures. The two different network microstructures significantly influenced mass transfer, protein adsorption, degradability, and contraction of the collagen hydrogels. Moreover, the cells presented distinct proliferation and morphology in the two hydrogels, which consequently modulated chondrogenic differentiation of BMSCs derived from rat. Collagen hydrogels with a fibrous network promoted more chondrogenic differentiation of BMSCs without additional growth factors in vitro and subcutaneous implantation in vivo than those with a porous network. Moreover, fibrous network resulted in less ECM calcification than porous network. However, the fibrous network could not prevent hypertrophy of the chondrogenic cells induced by BMSCs. Overall, these results revealed that the 3D network microstructure of a hydrogel was a key design parameter for the chondrogenic differentiation of BMSCs. Hydrogels had been used to induce the chondrogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) in cartilage tissue engineering, but the key design parameters remain unoptimized. This was mainly due to the different material properties including composition, strength, and microstructure, which would interplay with each other and result in difficulties to investigate the effects for one factor. In this study, we fabricated two collagen hydrogels with the same chemical composition and mechanical strength, but two distinct network microstructures. The effects of the two network microstructures on the chondrogenic differentiation of BMSCs were investigated by in vitro and in vivo assays. The results highlight the effects of network microstructures and provide important information about optimizing the design of future hydrogels in cartilage tissue engineering. [ABSTRACT FROM AUTHOR]

Abstract Liver dynamic contrast-enhanced MRI (DCE-MRI) requires high spatiotemporal resolution and large field of view to clearly visualize all relevant enhancement phases and detect early-stage liver lesions. The low-rank plus sparse (L + S) reconstruction outperforms standard sparsity-only-based reconstruction through separation of low-rank background component (L) and sparse dynamic components (S). However, the L + S decomposition is sensitive to respiratory motion so that image quality is compromised when breathing occurs during long time data acquisition. To enable high quality reconstruction for free-breathing liver 4D DCE-MRI, this paper presents a novel method called SMC-LS, which incorporates Sliding Motion Compensation into the standard L + S reconstruction. The global superior-inferior displacement of the internal abdominal organs is inferred directly from the undersampled raw data and then used to correct the breathing induced sliding motion which is the dominant component of respiratory motion. With sliding motion compensation, the reconstructed temporal frames are roughly registered before applying the standard L + S decomposition. The proposed method has been validated using free-breathing liver 4D MRI phantom data, free-breathing liver 4D DCE-MRI phantom data, and in vivo free breathing liver 4D MRI dataset. Results demonstrated that SMC-LS reconstruction can effectively reduce motion blurring artefacts and preserve both spatial structures and temporal variations at a sub-second temporal frame rate for free-breathing whole-liver 4D DCE-MRI. [ABSTRACT FROM AUTHOR]

Mutant SOD1 causes amyotrophic lateral sclerosis (ALS) by a dominant gain of toxicity. Previous studies have demonstrated therapeutic potential of mutant SOD1-RNAi delivered by intrathecal (IT) injection of recombinant adeno-associated virus (rAAV). However, optimization of delivery is needed to overcome the high degree of variation in the transduction efficiency and therapeutic efficacy. Here, on the basis of our previously defined, efficient IT injection method, we investigated the influence of injection speed on transduction efficiency in the central nervous system (CNS). We demonstrate that slow IT injection results in higher transduction of spinal cord and dorsal root ganglia (DRG) while fast IT injection leads to higher transduction of brain and peripheral organs. To test how these effects influence the outcome of RNAi therapy, we used slow and fast IT injection to deliver rAAVrh10-GFP-amiR-SOD1, a rAAV vector that expresses GFP and an artificial miRNA targeting SOD1, in SOD1-G93A mice. Both slow and fast IT injection produced therapeutic efficacy but the slow injection trended slightly toward a better outcome than the fast injection. These results demonstrate that IT injection speed influences the predominance of gene delivery at different CNS sites and should be taken into consideration in future therapeutic trials involving IT injection. [ABSTRACT FROM AUTHOR]

Geleophysic dysplasia, belonging to the group of acromelic dysplasia, is a rare genetic disease. Two genes, FBN1 and ADAMTSL2, were known to be linked to this disorder. The disorder presents as extreme short stature, short limbs, small hands and feet, stubby fingers and toes, joint stiffness, toe walking, skin thickening, progressive cardiac valvular thickening and characteristic facial features, including a round face with full cheeks. Here, we report the first Chinese case with geleophysic dysplasia type 1 based on clinical and genetic features. The boy was admitted because of severe physical growth retardation and mild motor retardation. Comprehensive medical evaluations were performed including metabolic studies, endocrine function examination, bone X-rays and echocardiography. Much delayed bone age and geleophysic dysplasia were found. Targeted next-generation sequencing was used to detect genetic mutations associated with skeletal dysplasia. Sanger sequencing was used to confirm the mutations in the patient. PCR amplification, cloing, and sequencing was used to determine the de novo mutation origin. Two compound heterozygous mutations were confirmed in the ADAMTSL2 gene of the patient. The c.340G > A (p.Glu114Lys) mutation was a de novo heterozygous mutation, and our results suggested that it was located on the paternal allele. While the c.234-2A > G inherited from his mother was a novel pathogenic heterozygous splicing mutation. Growth hormone deficiency had been observed in the patient. His growth velocity was improved by growth hormone supplementation. In conclusion, we have identified a novel splicing mutation of ADAMTSL2 carried by a Chinese boy with geleophysic dysplasia type 1. The patient was treated effectively with growth hormone supplementation. [ABSTRACT FROM AUTHOR]

Dopamine (DA) plays vital role in diagnosis and treatment of neurodegenerative disease. It is of high clinical relevance for developing simple, sensitive and selective DA detection method. But the electrochemical detection of DA still faces the problem of insufficient sensitivity, and generally need the complex material synthesis process to realize the selective detection of DA. In this work, we established a simple electrochemical surface plasmon resonance sensor for DA detection based on its electropolymerization property. The main interfering molecules of uric acid and ascorbic acid cannot undergo electropolymerization, while DA can produce polydopamine precipitation on the surface of Au film. The formation of polydopamine precipitation could amplify the SPR signal, and ensures the high selectivity and sensitivity of DA detection. The linear range is 0.01–1000 nM and the detection limit is as low as 1.4 pM. At the same time, this sensor has high selectivity for DA detection even in the presence of 50000-fold higher concentration of ascorbic acid and uric acid. Finally, the sensor was successfully applied to determine DA content in urine samples and DA released from PC12 cells under the stimulation of K+, demonstrating great potential in clinical applications. [Display omitted] • A very simple EC-SPR method was established for DA detection. • The electropolymerization property of DA was creatively used in its SPR detection. • The formation of polydopamine improves the detection limit of DA to 1.4 pM. • The method is highly selective for DA even with coexistence of 50,000-fold UA and AA. • The method can be used for DA detection in urine samples and PC12 cells. [ABSTRACT FROM AUTHOR]

Highlights: [•] Growth effects of elevated CO2 and drought on soybean are evaluated in pots under controlled conditions. [•] Elevated CO2 concentration improved soybean growth, Pn, WUE, even under drought condition. [•] Elevated CO2 concentration did not significantly improve yield under drought condition. [•] Soybean should be cropped under well irrigation regimes even if CO2 concentration elevated. [ABSTRACT FROM AUTHOR]

Thiamine metabolism dysfunction syndrome (THMD) comprises a group of clinically and genetically heterogeneous encephalopathies with autosomal recessive inheritance. Four genes, SLC19A3 , SLC25A19 , SLC19A2 , and TPK1 , are associated with this disorder. This study aimed to explore the clinical, biochemical and molecular characteristics of seven Chinese patients with THMD. Targeted next-generation sequencing of mitochondrial DNA and nuclear DNA was used to identify the causative mutations. The patients presented with subacute encephalopathy between the ages of 1–27 months. Brain magnetic resonance imaging (MRI) revealed abnormalities in the basal ganglia, indicating Leigh syndrome. Urine α-ketoglutarate in five patients was elevated. In four patients, five novel mutations (c.1276_1278delTAC, c.265A > C, c.197T > C, c.850T > C, whole gene deletion) were found in SLC19A3 , which is associated with THMD2. In two patients, four novel mutations (c.194C > T, c.454C > A, c.481G > A, and c.550G > C) were identified in SLC25A19 , supporting a diagnosis of THMD4. In one patient, two novel mutations (c.395T > C and c.614-1G > A) were detected in TPK1 , which is indicative of THMD5. The patients received thiamine, biotin, and symptomatic therapy, upon which six patients demonstrated clinical improvement. Our findings expanded the phenotypic and genotypic spectrum of THMD, with eleven novel mutations identified in seven Chinese patients. Early diagnosis and treatment have a significant impact on prognosis. [ABSTRACT FROM AUTHOR]

Primary hepatocellular carcinoma (HCC) is a common malignant tumor. Surgery is the main treatment, but HCC patients have a potential risk of tumor recurrence. Besides, many limitations arise during the application of single first-line antitumor drugs. Here, we selected Pluronic F-127 and sodium alginate (SA) to prepare a thermosensitive gel (Gel). The optimal synergistic ratio of PTX and DOX on the SMMC-7721 cells was 1: 2 (w/w), calculated by the Chou–Talalay analysis. Then, PTX and DOX coloaded liposomes (PD-LPs) with such drugs ratios presented enhanced anticancer ability in vitro. Upon local injection, the PD-LPs Gel formed a nanoparticles reservoir at tumor via sol–gel transformation, while exhibiting a long-term effective anti-tumor ability in vivo. The relative tumor volume after the PD-LPs Gel treatment was reduced over 62%. Effective mitochondria related apoptosis induction was observed. Therefore, the local delivery of PD-LPs Gel can be a promising alternative method for the HCC therapy. • The multi-drugs loaded liposomes system (PD-LPs) was prepared under best synergetic ratio of PTX and DOX found and validated by Chou–Talalay method in the SMMC-7721 hepatocellular carcinoma cells. • By uniting the PD-LPs and the thermosensitive gel, the locally injected PD-LPs Gel formed a reservoir at tumor, which increases and maintains local effective drugs concentration for long period in tumor region. • Components of PD-LPs Gel system are simple and highly biocompatible, giving it tremendous potential for clinical transformation • Largely enhanced therapeutic ability found in PTX and DOX combination is due to the effective induction of mitochondria apoptosis. Unlabelled Image [ABSTRACT FROM AUTHOR]

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder with two major subtypes, which are caused by AGPAT2 and BSCL2 mutations. Our aim was to further investigate the genetic features and clinical characteristics of infant patients with CGL. Three male infants and two female infants aged from one month to three months and unrelated with each other were involved in this study. Both whole-exome and Sanger sequencing were conducted, and variants were compared with in-house and public databases. The five infants with CGL displayed generalized lipodystrophy, skeletal muscle hypertrophy, hepatomegaly, hypertriglyceridemia, hyperinsulinemia, and liver dysfunction. Four patients (#2–5) showed more severe hypertriglyceridemia than Patient #1. A compound heterozygosity for novel frameshift mutations c.622_626delTCCTC and c.513delC in AGPAT2 was identified in Patient #1. Seven mutations in BSCL2 were found among Patients #2–5, in which splice site mutation c.404+1G > T, nonsense mutation c.402C > G, and frameshift mutation c.759_760delGA were novel. After medical treatment, metabolic parameters for all patients were under control. At the time of writing, they are seven to seventeen months old with much improved physical and cognitive development. Two novel mutations in AGPAT2 and three novel mutations in BSCL2 were identified from five unrelated infant patients diagnosed with CGL1 and CGL2. [ABSTRACT FROM AUTHOR]

Noonan syndrome is a common developmental disorder characterized by distinctive facial dysmorphism, short stature, congenital heart defects, pectus deformity, and developmental delay. It is related to the abnormal activation of genes involved in the RAS-MAPK signaling pathway, more than a dozen of which can be affected. However, mutations of the RRAS2 gene are rare, with only 6 different RRAS2 variants in 13 patients reported to date. In this case report, whole-exome sequencing revealed a novel heterozygous variant in the RRAS2 gene NM_012250: c.212G > A, p.(Gly71Glu). Phenotypically, our patient had typical Noonan syndrome-related clinical manifestations consistent with published reports, such as short stature, facial dysmorphism, short neck, patent foramen ovale, moderate global developmental delay, and hearing impairment. In addition, our patient also had a distal middle finger deformity and hair defect, which have not been reported in previous cases. We analyzed the clinical characteristics of all patients with Noonan syndrome caused by RRAS2 variants and reviewed the literature. This discovery expands the genetic and phenotypic spectrum of Noonan syndrome. [ABSTRACT FROM AUTHOR]

In this study, the local microstructure, strength and toughness of different zones in AA6061-T6 stationary shoulder friction stir welds were investigated. Results indicated that, the most significant weakening for both strength and toughness is found in HAZ that close to NZ. The microstructure of NZ includes recrystallized fine grains with high density of dislocations, homogeneous constituent particles distribution and re-precipitated of G.P. zones resulting in the recovery of local strength and the improvement for both plasticity and toughness. In HAZ, the grain structure and constituent particle distribution inherit the characteristics of base metal, but β″ precipitates are dissolved and the reprecipitated β′ particles are coarsened. This results in the decrease of yield strength, tensile strength, crack initial energy and propagation energy of HAZ, especially near NZ. [ABSTRACT FROM AUTHOR]

Injectable hydrogels are promising for treatment of bone defects in clinic owing to their minimally invasive procedure. Currently, there is limited emphasis on how to utilize injectable hydrogels to mobilize body's regenerative potential for enhancing bone regeneration. Herein, an injectable bone-mimicking hydrogel (BMH) scaffold assembled from nanocomposite microgel building blocks was developed, in which a highly interconnected microporous structure and an inorganic/organic (methacrylated hydroxyapatite and methacrylated gelatin) interweaved nano structure were well-designed. Compared with hydrogels lacking micro-nano structures or only showing microporous structure, the BMH scaffold enhanced the ingrowth of vessels and promoted the formation of dense cellular networks (including stem cells and M2 macrophages), across the entire scaffold at early stage after subcutaneous implantation. Moreover, the BMH scaffold could not only directly trigger osteogenic differentiation of the infiltrated stem cells, but also provided an instructive osteo-immune microenvironment by inducing macrophages into M2 phenotype. Mechanistically, our results reveal that the nano-rough structure of the BMH plays an essential role in inducing macrophage M2 polarization through activating mechanotransduction related RhoA/ROCK2 pathway. Overall, this work offers an injectable hydrogel with micro-nano structure driven bio-responsive abilities, highlighting harnessing body's inherent regenerative potential to realize bone regeneration. [Display omitted] [ABSTRACT FROM AUTHOR]