Cellular senescence of white adipose tissues (WAT) represents an early hallmark of aging; however, the involved mechanisms remain incompletely understood. Here, we identified the cytosolic phosphoenolpyruvate carboxykinase (Pck1) as a key regulator of mitochondrial function and inflammaging in WAT. Pck1 expression was downregulated in both gonadal WAT and inguinal WAT during aging, and adipocyte-specific Pck1 deficiency accelerated inflammaging and metabolic disorders. Untargeted metabolomic and isotope-tracing analyses revealed that loss of Pck1 impaired cataplerosis, the export of tricarboxylic acid (TCA) cycle intermediates, resulting in accumulation of fumarate in adipocytes. Supplementation with exogenous fumarate disrupted mitochondrial homeostasis of adipocytes, promoted oxidative stress and triggered cytosolic release of mitochondrial DNA (mtDNA), leading to the activation of the cyclic GMP-AMP synthase/stimulator of interferon genes (cGAS/STING) signaling pathway that may contribute to inflammaging and chronic obesity. These were phenocopied with Pck1-deficient adipocytes. Conversely, overexpression of fumarate hydratase (Fh1) reduced fumarate level substantially and attenuated adipocyte inflammaging. Collectively, these findings identify Pck1 as a pivotal regulator of mitochondrial metabolic homeostasis and suggest that targeting Pck1 may represent a promising therapeutic strategy for age-related diseases.

Tissue regeneration is a central frontier in biomedicine, yet articular cartilage defect repair in osteoarthritis (OA) remains a formidable challenge. Although mesenchymal stem cell (MSC)-based therapies show great potential for cartilage regeneration, their clinical translation is hindered by sequential barriers: low cell retention, oxidative stress-induced apoptosis, and inefficient MSC homing to defect sites and subsequent integration. Herein, we fabricate chondrogenic niche hydrogel microspheres (Chonichspheres) via microfluidics. These HMs are composed of gelatin methacryloyl (GelMA)/aldehyde-hyaluronic acid methacrylate (AHAMA) composite matrices loaded with amino fullerenes (AF) and transforming growth factor-β3 (TGF-β3). Chonichspheres exert four synergistic functions: GelMA acts as a structural scaffold to promote MSC adhesion; AF exert sustained antioxidant effects to regulate redox homeostasis in MSCs and OA chondrocytes; AHAMA enables precise targeted homing and tissue integration; and TGF-β3 induces MSC chondrogenic differentiation. Validated by an HM-adapted custom microphysiological system (MPS) and in vivo experiments, Chonichspheres activate the integrin-PI3K-AKT-mTOR axis, protecting MSCs and facilitating chondrogenic differentiation under OA-mimicking dynamic culture conditions. By synergizing active covalent tissue integration with durable, non-sacrificial antioxidant defense, this programmatic platform provides a robust precision regenerative strategy for OA cartilage repair.

Immunomodulatory microspheres represent an advanced class of biomaterials that function as comprehensive platforms integrating passive drug delivery and active immunoregulatory capabilities. This review synthesizes fundamental design principles-where engineered chemical (e.g., ion release, surface functionalization, redox modulation) and physical (e.g., size, morphology, stiffness) properties synergistically create "immune instruction systems" to reprogram pathological microenvironments. Their transformative applications span multisystem diseases. In orthopedics, microspheres recalibrate macrophage polarization (M1/M2) to resolve osteoarthritis inflammation and promote bone regeneration in osteoporosis. In gynecology, they overcome mucosal barriers to target ectopic lesions in endometriosis and enhance immunotherapy for Premature Ovarian Insufficiency. Moreover, in neurology, they penetrate the blood-brain barrier (BBB) to mitigate neuroinflammation in Alzheimer's disease and stroke. Despite its promise, clinical translation faces challenges, including tissue-specific delivery barriers (e.g., joint clearance, cervical mucus, and BBB penetration) and immune-related safety risks (e.g., cytokine release syndrome). Emerging solutions include stimulus-responsive designs, exosome-microsphere hybrids, and personalized formulations based on immune profiling. Future advancements require scalable manufacturing and long-term safety validation to realize the full potential of these platforms in precision immunotherapy.

Licorice, a widely used herb in food additives and nutraceuticals, primarily exerts its biological effects through 18β-glycyrrhetinic acid (18β-GA) in vivo. Here, we aimed to investigate whether 18β-GA attenuates obesity-associated white adipose tissue (WAT) inflammaging and to clarify the molecular events responsible for its protective effects. Using a high-fat diet mouse model together with cultured adipose progenitor cells (APCs), we found that 18β-GA significantly mitigated inflammation and cellular senescence in WAT, diminished the expression of senescence-associated secretory phenotype (SASP), and restored APC adipogenic differentiation potential. Network pharmacology analysis pinpointed HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) as a key candidate target, with subsequent experiments confirming that the anti-inflammaging effect of 18β-GA was comparable to established HMGCR inhibitors. Furthermore, 18β-GA markedly reduced cholesterol accumulation in WAT, which directly induces APC senescence, suggesting that cholesterol homeostasis regulation represents a key mechanism responsible for its protective activity. Thus, 18β-GA emerges as a promising nutraceutical agent for combating obesity-driven metabolic disorders and chronic inflammation in WAT.

Metabolism-regulating microspheres have evolved from conventional drug carriers into active platforms capable of spatiotemporally reprogramming pathological metabolic networks. Chronic diseases are increasingly understood to be driven by metabolic dysregulation, highlighting the need for therapeutic strategies that enable localized and precise metabolic intervention. This review systematically outlines the core design principles of these microspheres, emphasizing the synergistic integration of engineered chemical properties, such as ionic signaling, metabolite delivery, and pathway modulator release, with tailored physical characteristics, including stiffness, porosity, and size of the microspheres. Together, these features construct “metabolic instruction systems” that correct dysregulated pathways at the tissue level. Their versatile applications include orthopedic diseases, such as osteoporosis, osteoarthritis, and bone defects; ophthalmic conditions, including glaucoma and diabetic retinopathy; and gynecological disorders, such as premature ovarian insufficiency, ovarian cancer, and endometriosis. These systems target key metabolic abnormalities, such as glycolytic dysregulation, mitochondrial dysfunction, and oxidative stress, which are recognized as central drivers of disease pathogenesis across multiple organ systems. Despite considerable progress, clinical translation remains limited by tissue-specific delivery barriers, interindividual metabolic heterogeneity, and long-term safety concerns within dynamic metabolic networks. Emerging strategies, such as personalized formulations, artificial-intelligence-driven designs, and organ-on-a-chip validation platforms, are being developed to address these challenges. With ongoing interdisciplinary innovation, metabolism-regulating microspheres hold great promise as precise therapeutic modalities for a spectrum of chronic diseases rooted in metabolic imbalance, offering targeted and sustained metabolic correction.

Abstract Background Autologous and allogeneic bone grafts are primarily used for bone tissue defects; however, they have limitations such as limited supply, donor site morbidity, and immune rejection risks. Therefore, substitute synthetic bone grafts are required. Methods Using low-temperature 3D printing combined with freeze-drying technology, a hierarchically porous PLGA/HA@SeNPs composite scaffold was fabricated by compositing poly(lactic-co-glycolic acid) (PLGA) with hyaluronic acid-modified selenium nanoparticles (HA@SeNPs), enabling sustained immunomodulation and osteogenic activity through its engineered microtopography and bioactive components. Results In vitro evaluations confirmed that the unique microstructure and sustained selenium release from HA@SeNPs synergistically promoted macrophage polarization toward the M2 phenotype, accompanied by enhanced osteogenic differentiation as shown by upregulation of Runx2 and OCN and accelerated matrix mineralization. Implantation into a rat femoral critical-sized defect model resulted in substantially improved bone repair and architectural restoration. Conclusions These findings indicate that the intrinsic physicochemical properties of the PLGA/HA@SeNPs scaffold orchestrate a favorable osteo-immune environment, positioning it as a promising platform for bone regeneration.

Red blood cell (RBC) transfusion is a core clinical intervention. However, hypothermic storage induces progressive biochemical, structural, and functional impairments collectively termed the RBC storage lesion (RSL), which compromises post-transfusion efficacy and safety. Conventional RSL detection relies on bulk population-averaged indicators with low physiological relevance and no single-cell resolution, failing to capture cellular heterogeneity and microcirculatory dysfunction. Lab-on-a-chip (LOC) platforms are established with microfluidic technology, and organ-on-a-chip represents a biomimetic and advanced extension of such systems. Together, they enable biomimetic reconstruction of the in vivo microcirculatory microenvironment, high-throughput single-cell analysis, and quantitative assessment of RBC mechanical phenotypes under physiological shear conditions. Distinct from fragmented prior reviews that separate microfluidic engineering from transfusion clinical demands, this work systematically outlines the molecular mechanisms and clinical impacts of RSL alongside unresolved detection bottlenecks, and builds an integrated LOC-endothelium-on-a-chip technical framework covering structural design, biocompatible material screening, and standardized fabrication workflows. It further summarizes microfluidic core applications including single-cell deformability quantification, stiffness evaluation, hemolysis susceptibility testing, microvascular occlusion simulation, and RBC-endothelial interaction analysis. Uniquely, it constructs a tiered translational roadmap integrating microfluidics with multi-omics, artificial intelligence, vascularized multi-organ chips, and function-centered pre-transfusion surveillance, and proposes microfluidic strategies to optimize RBC storage regimens. In summary, microfluidic technology overcomes the limitations of conventional assays for RSL quality control, provides an emerging technical platform for RSL mechanistic research, pretransfusion quality evaluation, and donor-specific precise matching, and promotes the transformation of transfusion medicine from time-based empirical management to function-oriented precision practice.

Rheumatoid arthritis (RA) is a chronic autoimmune disease that severely impairs the quality of life of patients owing to its complex immunopathological mechanisms and persistent joint damage. In recent years, the application of biomaterials in regulating immune responses in RA has attracted extensive attention, particularly regarding the regulatory effects of their physicochemical properties, including surface chemistry, mechanical properties, and morphology, on immune cell behavior and the inflammatory microenvironment. Current studies have revealed that rationally designed biomaterials can modulate inflammatory responses by influencing the activation, differentiation, and signaling pathways of immune cells, thereby providing novel insights into RA treatment. However, the specific regulatory mechanisms underlying different physicochemical properties remain incompletely elucidated, and related research still faces challenges related to material biocompatibility and immune specificity. This article systematically reviews the latest advances in the research of biomaterial physicochemical properties in the field of RA immunomodulation, analyzes the mechanisms of their action in regulating the immune microenvironment, and discusses the potential and future directions of biomaterial-based immunomodulatory strategies in clinical applications to provide theoretical basis and technical support for the development of precision immunotherapy.

Sarcopenia is a degenerative skeletal muscle disorder closely associated with aging, characterized by the gradual loss of muscle mass and function, which severely impacts the quality of life in the elderly. In general, the severity of sarcopenia varies significantly among different patients and across different muscle groups, which increases the complexity and challenge of sarcopenia treatment. Based on the core pathological mechanism of sarcopenia, namely the deficiency of Nicotinamide adenine dinucleotide (NAD(+)) induced mitochondrial dysfunction, this study has developed a novel Energy-replenishing hydrogel microsphere (NMN@Lipo-s@AHM) for the targeted delivery of Nicotinamide Mononucleotide (NMN) to muscle cells through local injection. The stability of NMN was enhanced through liposomal encapsulation, peptide SS-31 was applied for mitochondrial targeting, and sustained local releasing was achieved via aldehyde hyaluronic acid methacrylate hydrogel microspheres (AHM). In vitro and in vivo experiments demonstrated that the Energy-replenishing hydrogel microspheres significantly alleviated dexamethasone-induced mitochondrial dysfunction and senescent phenotypes in muscle cells. Transcriptomic and proteomic analyses revealed that the hydrogel microsphere regulates mitochondrial function by activating the “AMPK-SIRT1-PGC1α” signaling pathway, thereby synergistically improving mitochondrial energy metabolism and cellular senescence. This study not only provides an efficient targeted delivery strategy for NAD+ supplementation but also offers new directions for the mechanistic research and clinical intervention of sarcopenia.

Organoids—three-dimensional, self-organizing living micro-tissue entities—are fundamentally reshaping the outcome of modern biomedical research through their remarkable capacity to recapitulate the topographical complexity and physiological fidelity of native tissues. Additionally, organoids are able to recapitulate the genetic and epigenetic signature of individual human beings, which is a crucial stepping stone for all personalized and regenerative medicine approaches. However, despite their ability to express selected lineage-specific markers, existing organoid culture platforms exhibit fundamental deficiencies in the spatiotemporal precision of extracellular matrix (ECM) and pericellular matrix (PCM) organization—a vexating limitation rooted in the absence of sophisticated spatiotemporal mechano-coding. Consequently, organoids frequently remain arrested in immature phenotypic states, severely constraining their translational efficacy in regenerative medicine. Addressing this critical bottleneck, hydrogel microsphere-mediated engineering strategies have emerged as a transformative paradigm. This review centers on innovative approaches with a focus on osteomuscular organoid models, elucidating their rational biomaterial design principles, unique mechano-coding advantages, and the core mechanisms by which they orchestrate the secretion and microstructural remodeling of endogenous ECM/PCM components. We conclude by prospectively exploring the potential of these microsphere-mediated systems to enhance their physiological accuracy and clinical translatability of in vitro musculoskeletal models.

Current strategies for cartilage repair, including decellularized cartilage matrices and synthetic bioactive materials, often encounter challenges such as immune responses and donor morbidity. In this study, we optimized an extracellular matrix (ECM) derived from mesenchymal stem cells through preconditioning with disease-associated inflammatory factors, specifically interleukin 6, tumor necrosis factor alpha, and interferon gamma (IFN-γ). Our in vitro experiments demonstrated that the cytokine-preconditioned stem-cell-derived ECM, especially IFN-γ-ECM, supports chondrocyte homeostasis by restoring mitochondrial energy metabolism. Furthermore, bioactive molecules secreted from this preconditioned ECM boost the recruitment of endogenous stem cells and facilitate their differentiation into chondrocytes. Notably, we found that IFN-γ-ECM facilitates the chondrogenic differentiation of mesenchymal stem cells through the activation of the integrin/phosphatidylinositol 3-kinase/Akt pathway and the Smad2/3 signaling cascade. These results highlight the potential of the cytokine-stimulated ECM, especially IFN-γ-ECM, to restore chondrocyte homeostasis, optimize the mobilization of endogenous stem cells, and substantially improve the regeneration of cartilage defects, offering a promising strategy for acellular cartilage graft reconstruction.

With the accelerating pace of population aging, the incidence of osteoarthritis (OA), a degenerative disease strongly associated with age, is rapidly increasing. Chondrocyte senescence is a major contributor to cartilage degeneration; however, effective therapeutic strategies targeting chondrocyte aging remain lacking. Mesenchymal stem cell (MSC)-based approaches have emerged as a promising means of combating cellular senescence, among which exosomes (Exos) play a pivotal role in mediating therapeutic effects. Compared with direct MSC transplantation, Exos offer a safer and more ethically acceptable alternative. Moreover, the functional properties of Exos can be modulated by the microenvironmental stimuli applied to MSCs, although the underlying molecular mechanisms remain largely unclear. In this study, we employed interferon-γ (IFN-γ) to precondition MSCs and generate functionally enhanced Exos (iExos). Both in vitro and in vivo experiments demonstrated that iExos exhibit superior antisenescent activity in chondrocytes and more effectively attenuate OA progression. Sequencing analysis, together with mechanistic studies, revealed that iExos exert these effects by sustaining mitochondrial AMPK-SIRT3 homeostasis in chondrocytes through Hsp70. These findings partially elucidate a key pathway by which stem cell-derived iExos combat chondrocyte senescence and may inform the design of stable, efficient, and safe MSC-based antisenescence strategies.

Coaxial three-dimensional (3D) printing enables precise, multi-material deposition, demonstrating strong potential across diverse fields, including industrial monitoring, health sensing, artificial intelligence (AI) hardware, and food packaging. Its core value is prominently realized in the biomedical domain, where it has revolutionized tissue engineering. The present review consolidates advancements in 3D coaxial bioprinting across diverse biomedical applications, focusing on its transformative potential in vascularized tissue engineering, spatiotemporal drug delivery, and patient-specific disease modeling. This review also explored unresolved challenges, such as bioink optimization and functional vascularization, while proposing integrative solutions that combine coaxial printing with AI and hybrid fabrication strategies. The versatility of coaxial 3D printing is evident in its numerous biomedical applications, such as cardiovascular tissue engineering, skin regeneration, bone repair, and functional muscle constructs. In bone tissue engineering, coaxial printing facilitates vascularization and osteochondral regeneration through spatially controlled bioink and scaffold design. Applications extend to cartilage repair, neuromuscular junction modeling, and tumor microenvironment replication. Despite progress, challenges persist in optimizing bioink rheology, achieving functional vascularization, and scaling production for clinical application. Notably, the integration of advanced materials, such as hydrogels and inorganic salts, with hybrid strategies, including electrospinning and sacrificial printing, highlights the synergistic potential of coaxial bioprinting to transform regenerative medicine, drug screening, and personalized therapies. Ongoing innovations in multi-scale, multi-cellular printing can bridge the gap between engineered constructs and biological functional tissues.

BACKGROUND:The global burden and trend of musculoskeletal disorders (MSDs) in postmenopausal women (PMW) remain unclear. METHODS:Using the Global Burden of Disease (GBD) 2021 data, this study assessed the prevalence and disability-adjusted life years (DALYs) for rheumatoid arthritis (RA), osteoarthritis (OA), low back pain (LBP), neck pain (NP), gout, and other musculoskeletal conditions (OMSKDs) from 1990 to 2021. Bayesian Age-Period-Cohort (BAPC) models projected trends to 2045. Health inequalities were analyzed using the Slope Index of Inequality (SII) and the Concentration Index, with decomposition methods identifying the drivers of burden changes. RESULTS:From 1990 to 2021, the age-standardized prevalence and DALYs rates have significantly increased among PMW, with OA and LBP being the primary contributors to this burden. These increases were primarily driven by population growth. Specifically, RA, OA, and gout accounted for more than 50% of the total burden in women across all age groups, with RA burden being 1.2 times higher than that in premenopausal women, OA 3.1 times higher, and gout 2.9 times higher. Notably, in PMW, the burden of gout was 74%. The burden of gout is strongly correlated with the Socio-Demographic Index (SDI), particularly in high-income regions, such as North America, where the United States exhibits the highest DALYs rates. Furthermore, projections indicate that by 2045, the global burden of MSDs could double, with OA potentially affecting nearly 50% of the PMW. CONCLUSION:From 1990 to 2021, the global burden of MSDs among PMW has risen significantly, with notable regional disparities underscoring the critical need for tailored preventive strategies to alleviate the worldwide impact of these conditions.

The imbalance of immune factor secretion plays a critical role in the dysregulation of immune homeostasis, contributing to chronic inflammation and impaired tissue regeneration. Nanofiber microstructures have emerged as promising biomaterials in tissue regeneration due to their ability to modulate immune cell behavior. However, the mechanisms by which nanofiber microstructures regulate immune factor secretion remain poorly understood. In this study, we fabricated three types of nanofibers with varying degrees of alignment microstructures and investigated their effects on immune factor secretion of immune cells. In vitro analyses revealed that highly aligned nanofibers significantly enhanced the secretion of anti-inflammatory factors such as TGF-β1 and IL-10, while suppressing pro-inflammatory factors including TNF-α and IL-6. These effects were mediated through the modulation of immune cell adhesion receptors and mechanotransduction pathways. Furthermore, in vivo experiments demonstrated that highly aligned nanofibers optimized the immune microenvironment at wound sites, promoting angiogenesis and accelerating tissue regeneration. This study introduces an alternative perspective on biomaterial-based immune regulation, highlighting the critical role of nanofiber microstructures in directing immune cell functions. These findings provide a foundation for the rational design of biomaterials with tailored microstructures to achieve precise immune modulation, offering strategies for enhancing wound healing and advancing regenerative medicine. STATEMENT OF SIGNIFICANCE: Dysregulated immune factor secretion is a major contributor to chronic inflammation and impaired tissue regeneration. Current strategies that rely on exogenous cytokines are constrained by short half-lives and uncontrollable release kinetics. Given that immune cells are the primary source of these factors, direct modulation of their local secretory profiles offers a more stable and sustained alternative. Here, we introduce a nanofiber microstructure-based approach to program immune cell secretory behavior. We demonstrate, for the first time, that highly aligned nanofibers remodel the immune secretome via the integrin α10β1/PI3K/AKT signaling pathway, thereby reestablishing a pro-regenerative immune microenvironment and enhancing tissue repair. This study establishes a new paradigm in which biomaterials precisely reprogram immune secretory function, laying the foundation for programmable immunoregulatory materials with strong translational potential.

BACKGROUND:Targeting metabolic disorders has emerged as a promising therapeutic strategy in the treatment of chronic kidney disease (CKD). 18β-glycyrrhetinic acid (18β-GA) is known for its metabolic regulatory and antioxidant effects in various diseases. However, the precise effects and underlying mechanisms of 18β-GA on CKD remain unclear. PURPOSE:This study aims to evaluate the therapeutic efficacy of 18β-GA on CKD and to identify the molecular targets of 18β-GA with a particular emphasis on its role in metabolic regulation. STUDY DESIGN AND METHODS:A high-fat diet-induced CKD model was established to investigate the influence of 18β-GA on lipid metabolic disorders, cellular senescence and fibrosis in the kidneys. Co-immunoprecipitation was performed to investigate the impact of 18β-GA on the interaction between transcription factor EB (TFEB) and sirtuin 1 (SIRT1). Additionally, network pharmacology and molecular docking analyses were conducted to identify the specific target proteins of 18β-GA. RESULTS:18β-GA alleviated renal lipid accumulation, tubular cell senescence and renal interstitial fibrosis in CKD mice. Treatment with 18β-GA largely restored mitochondrial function and attenuated intracellular lipotoxicity and associated cellular senescence by promoting lipophagy in renal tubular cells. Mechanistically, 18β-GA acting as a partial antagonist of peroxisome proliferator-activated receptor gamma (PPARγ) enhanced lipophagy through SIRT1-mediated nuclear translocation of TFEB which induced the expression of microtubule-associated protein light chain 3 (LC3). CONCLUSION:Our findings demonstrate that 18β-GA, functioning as a partial antagonist of PPARγ, counteracts CKD progression by activating the SIRT1-TFEB-LC3 signaling axis-mediated lipophagy and thus uncover a novel mechanism by which 18β-GA improves renal lipid metabolism disorders and exerts renoprotective effects. These results highlight the potential of 18β-GA as a promising therapeutic agent for the treatment and prevention of CKD.

Lactylation, a recently discovered histone and non-histone modification driven by lactate, has redefined the understanding of how metabolic by-products regulate gene expression. Beyond its conventional role as an energy substrate, lactate emerges as a pivotal signaling mediator that couples cellular metabolism with epigenetic regulation. In musculoskeletal disorders, aberrant lactylation has been implicated in the disruption of osteogenic-osteoclastic balance, extracellular matrix homeostasis, and regenerative capacity, thereby linking cellular metabolic stress to pathological tissue remodeling. These findings position lactylation as a unifying mechanism across osteoporosis, osteoarthritis, intervertebral disc degeneration, and sarcopenia. Yet, the field remains in its infancy: the enzymatic machinery of lactylation is incompletely characterized, context-specific functions are poorly defined, and translation to human pathology is scarce. Conceptualizing lactylation as a metabolic-epigenetic nexus not only reframes our understanding of musculoskeletal biology but also highlights new opportunities for biomarker discovery and targeted epigenetic therapies. Addressing these challenges will be essential to harness the clinical potential of this emerging regulatory paradigm.

The disruption and limited reconstruction capacity of the osteocyte network are pivotal factors underlying impaired bone regeneration. This study developed an injectable mineralized hydrogel microsphere that provides a mineral-rich environment and optimal matrix stiffness for osteocyte network restoration. Furthermore, it spatially activates Notch signaling through osteocyte-derived vesicles with high Jagged1 expression, promoting osteocyte differentiation and enhancing angiogenic regulatory function. Specifically, hydrogel microspheres combining gelatin methacrylate (GelMA), alginate methacrylate (AlgMA), and osteocyte membrane vesicles (OMVs) were fabricated via gas-shear microfluidics and photopolymerization, followed by in situ pre-mineralization to produce mineralized microspheres. Findings indicate that mineralized hydrogel microspheres exhibit significantly increased compressive modulus and in situ formation of amorphous calcium phosphate particles within the gel matrix. In vitro, the mineralized microspheres effectively facilitated osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs), with adherent cells displaying accelerated osteocyte marker expression. Co-culture experiments further revealed enhanced vascular formation potential. Ectopic bone regeneration studies demonstrated that mineralized hydrogel microspheres promote rapid formation of mature osteocyte networks in vivo. Moreover, in a femoral critical bone defect model, these microspheres accelerated defect healing. Collectively, mineralized hydrogel microspheres expedite osteocyte network reconstruction, supporting intelligent bone regeneration, and present a promising approach for critical-sized bone defect repair.