Iron oxide nanozymes with intrinsic peroxidase-like activity and excellent biosafety are considered ideal agents for inducing tumor ferroptosis. However, their practical catalytic efficiency is often constrained by an inherent delocalized electronic structure and the restrictive tumor antioxidant microenvironment. Herein, we report a magnetic field-mediated strategy to synthesize ultra-small superparamagnetic manganese-doped iron oxide (USMIO) nanoparticles with precisely tailored multi-enzyme activities (denoted as MUSMIO). The magnetic field in situ generated abundant oxygen vacancies and optimized the Mn/Fe coordination environment, significantly boosting electron transfer and catalytic performance. MUSMIO exhibited robust pH-responsive peroxidase-like activity with a hydroxyl radical yield ∼5.86-fold higher than pure ultra-small superparamagnetic iron oxide (USIO) and ∼2.43-fold higher than USMIO, together with favorable catalase-, glutathione oxidase-, and nicotinamide adenine dinucleotide phosphate oxidase-like activities. This synergistic multi-enzyme cascade efficiently blocked glutathione regeneration, relieved tumor hypoxia, and triggered a sustained hydroxyl radical storm to drive extensive lipid peroxidation and selective ferroptosis in cancer cells, while exhibiting negligible toxicity to normal cells. In a murine breast cancer model, MUSMIO achieved complete tumor regression with no recurrence, and prolonged the median survival time of mice with excellent biosafety. This work provides a generalizable physical-field-assisted route for designing high-performance multi-enzyme mimetic nanozymes for targeted tumor therapy.

Organoids are microscopic 3D structures that resemble real organs, assembled in vitro from stem cells. Since the Dutch team of Hans Clevers successfully cultured intestinal stem cells to generate intestinal structures in 2009, organoid technology has developed rapidly, and culture protocols covering various organs such as the brain, liver, intestine, kidney, and bone have been established. These micro-organ models retain the cellular heterogeneity, tissue-specific structure, and genetic background of the original tissue. Compared to traditional two-dimensional culture, they provide a more physiologically relevant research platform. This article reviews organoid generation strategies, mainly dividing them into scaffold-free and scaffolded methods, and details specific generation protocols for brain, liver, intestine, kidney, and bone organoids. Furthermore, this article emphasizes innovations in bioengineering, such as organ-on-a-chip systems and 3D bioprinting technology. These technologies can enhance the maturity, vascularization, and reproducibility of organoids. The article also extensively discusses the biomedical applications of organoids, including in vitro disease models, infectious diseases, cancer, drug screening and toxicity testing, tissue engineering, and age-related diseases. Despite the significant potential of organoids, some challenges remain. Issues such as standardization, limited vascularization, ethical considerations, and scalability for industrial and clinical translation remain. Looking ahead, interdisciplinary efforts integrating stem cell biology, bioengineering, and computational methods promise to drive the development of organoid technology. This will make it a more robust and physiologically consistent model. Organoids hold the potential to become a cornerstone tool in biomedical research, bridging the gap between in vitro research and the clinical application of personalized medicine, drug development, and regenerative therapies.

Gastric injury repair poses a significant clinical challenge due to the ongoing exposure to gastric acid, complex mechanical environments, and intense inflammatory responses. To address these issues, we developed a bioactive asymmetric Janus hydrogel (PSE/GDMA-BPN@Ori) that features strong wet adhesion, immunomodulatory properties, and regenerative potential for repairing gastric injuries. This hydrogel consists of a bilayer: an anti-adhesive layer made from electrospun polycaprolactone/decellularized small intestinal submucosa (PCL/dSIS-ECM) and a dopamine-modified gelatin methacrylate (GDMA) adhesive layer, which is functionalized with black phosphorus nanosheets (BPN) and loaded with the natural flavonoid orientin (Ori). This configuration allows for one-sided wet adhesion, mechanical robustness, and controlled drug release. The hydrogel demonstrates excellent biocompatibility, antioxidant capacity, hemostatic performance, and in vivo biodegradation. In vitro studies show that it effectively scavenges reactive oxygen species and promotes macrophage polarization toward the M2 reparative phenotype. In a rat model of gastric perforation, the hydrogel significantly accelerated mucosal regeneration, enhanced angiogenesis, and reduced postoperative inflammation and adhesion formation. Overall, this multifunctional Janus adhesive hydrogel integrates wet adhesion, immune regulation, and bioactive repair, facilitating rapid and stable gastric tissue healing. It presents a promising biomaterial alternative for treating gastric perforations and anastomotic leakage.

Conventional magnetic assembly strategies for hydrogel constructs face fundamental limitations in achieving multiscale structure construction due to transient magnetic response and lack of magnetic domain programming. We present a hierarchical assembly strategy utilizing magnetic memory liquid droplets as guidable building blocks for heterogeneous hydrogel structures. Through interfacial jamming of alginate-surfactant membranes and subsequent photo-crosslinking, we engineer ferromagnetic liquid droplets containing polyethylene glycol (PEG)-modified iron oxide nanoparticles that exhibit magnetic memory. These units enable hierarchical assembly via sequential magnetization and re-magnetization cycles. The molded building block can be reconfigured using induction magnetic dipoles, which determine the building block's magnetic assembly and actuation behavior. Meanwhile, by adjusting the intensity and direction of the external magnetic field, the assembly can perform directional delivery in narrow and tortuous spaces. These biocompatible, complex, and multifunctional hydrogel assemblies can be readily applied to tissue engineering, regenerative medicine, and biomimetics. STATEMENT OF SIGNIFICANCE: Fabricating complex, biocompatible hydrogels with spatial control remains a challenge in tissue engineering. Conventional magnetic assembly methods are limited by transient magnetic responses and lack programmable domain control, hindering multiscale heterogeneous structure formation. This work presents a hierarchical magnetic assembly strategy using magnetized liquid droplets with magnetic memory, enabling heterogeneous hydrogel construction through magnetization-remagnetization cycles, actuation, and reconfiguration under external fields. The strategy's effectiveness is demonstrated by fabricating a blood vessel tissue mimic.

Alzheimer’s disease (AD) is characterized by progressive neurodegeneration, neuroinflammation, and systemic comorbidities, yet disease-modifying therapies remain elusive. Here, we show that partial epigenetic reprogramming via brain-restricted expression of Oct4, Sox2, and Klf4 (OSK) restores neuronal and neuroimmune homeostasis without loss of cellular identity. In APP/PS1 mice, OSK reprogramming improves cognitive performance across disease stages, reduces amyloid-β deposition, attenuates microglial activation, preserves synaptic integrity, and limits neuronal apoptosis. Mechanistically, reduced representation bisulfite sequencing reveals widespread reversal of AD-associated DNA methylation patterns, which is dependent on Tet2-mediated demethylation, establishing epigenetic rejuvenation as a key driver of functional recovery. Unexpectedly, brain-restricted OSK reprogramming also ameliorates systemic bone loss by reshaping brain-derived extracellular vesicle signaling, including modulation of miR-483-5p, thereby restoring osteogenic capacity. Together, these findings identify partial epigenetic reprogramming as a strategy to rewire neuro-immune circuits and link central nervous system rejuvenation to peripheral tissue homeostasis, providing a conceptual framework for targeting both neurodegeneration and its systemic consequences in AD.

To develop and validate a cartilage organoid (CO)-laden digital light processing (DLP) bioprinting strategy for auricular reconstruction and to compare its performance with conventional chondrocyte-laden prints. Rat bone-marrow stromal cells (BMSCs) were aggregated into spheroid and chondrogenically induced to form CO. Organoid construction and characterization included EdU proliferation assay, CD73/CD90 immunofluorescence (IF), and real-time quantitative polymerase chain reaction (qPCR) of chondrogenic genes. O-nitrobenzyl functionalized gelatin (GelNB)/ methacrylated hyaluronic acid (HAMA) bioinks were screened by gross morphology, tensile/ compressive mechanics, enzymatic degradability (0.1

With the rapid progression of global population aging, osteoarthritis (OA), a common degenerative joint disease, increasingly affects the quality of life and functional status of the elderly. OA often coexists with other chronic diseases in elderly patients, forming a complex comorbidity network. However, the interactions between OA and other geriatric comorbidities and their effects on disease progression have not been fully explored. This review investigates the pathological mechanisms of OA within the geriatric comorbidity network, focusing on its bidirectional interactions with osteoporosis, obesity, diabetes, and hypertension, and examines the effects of commonly used medications in elderly patients with comorbidities. The findings reveal that these chronic conditions contribute to OA through mechanisms such as mechanical stress, metabolic dysregulation, and inflammation. Additionally, OA exacerbates other comorbidities, further worsening the overall health of patients. The review emphasizes the need for integrated treatment strategies that address both OA and its comorbidities, and highlights the importance of further research into the molecular interactions between OA and comorbidities for more effective treatment strategies, particularly targeting shared pathways. Translational Potential of this Article: This review defines osteoarthritis (OA) as a systemic disease driven by organ crosstalk within the geriatric comorbidity network. Interactions among bone, adipose, vascular, and metabolic systems converge on shared pathways, including inflammation, metabolic dysregulation, and biomechanical imbalance. This framework supports a shift toward mechanism-based, multi-organ management and highlights opportunities for drug repurposing, biomarker-guided risk stratification, and precision medicine, ultimately improving outcomes in elderly patients with OA and multimorbidity.

Brain health is closely linked to bone homeostasis. Skeletal aging is characterized by inadequate bone formation and marrow adiposity, but whether the brain contributes to this imbalance remains unknown. This study shows that aged brain neurons, mainly those in the hippocampus and cerebral cortex, produce excess WD repeat and FYVE domain containing 1 (WDFY1) protein and transfer it to the bone via extracellular vesicles (EVs), leading to bone-fat imbalance and osteoporosis. Increasing brain Wdfy1 expression causes premature skeletal aging. Conversely, suppressing Wdfy1 in the whole brain, hippocampus or neurons, genetically deleting neuronal Wdfy1, and selectively inhibiting neuronal EV release all improve bone health. Mechanistically, WDFY1 binds to the retromer complex to promote the endosome-to-Golgi recycling of cathepsin D and peroxiredoxin 2, thus inhibiting osteogenesis and augmenting adipogenesis. This study identifies the role of aged brain neuronal EVs as an important messenger in triggering bone-fat imbalance by transferring WDFY1 to bone. Chen et al. identify a brain-to-bone communication axis whereby extracellular vesicles from aged brain neurons transport WDFY1 protein to distal bone, driving bone-fat imbalance and promoting osteoporosis.

Breast reconstruction is essential for restoring self-image and quality of life after mastectomy. While current methods using implants or autologous tissue are prevalent, they face challenges such as capsular contracture and volume loss. This review explores how bio-fabrication strategies are generating innovative scaffolds to overcome these limitations. We discuss the clinical use of bio-fabrication and detail preclinical progress in key areas: enhancing the biocompatibility and safety of implants, achieving soft tissue regeneration and vascularization, integrating antitumor therapy with reconstruction, and optimizing aesthetic outcomes. Finally, we outline future research directions for developing superior biomaterials to advance breast reconstruction. Statement of Significance Current breast reconstruction methods are limited by complications, such as capsular contracture, volume loss, and infection. This review underscores the promise of bioengineered scaffolds, where biomaterials combined with bioactive agents and advanced fabrication (e.g., 3D printing) can recreate the natural breast microenvironment to support regeneration. This replication is crucial for promoting vascularization, adipogenesis, and tissue integration. Furthermore, we explore new strategies for modifying implant surfaces to minimize fibrosis and infection risks. This work serves as a guide for developing next-generation regenerative scaffolds and highlights their potential to significantly improve clinical outcomes in breast reconstruction by providing personalized, biocompatible, and functionally' as none of the work so far in the literature can truly replicate the natural breast microenvironment.

Intestinal homeostasis is essential for systemic health and longevity, and its disruption contributes to colitis and age-related gut dysfunction. N-acetylneuraminic acid (Neu5Ac), a major form of sialic acid enriched in bird's nest and human milk, exhibits immunomodulatory and antioxidant properties, yet its physiological role in intestinal integrity remains unclear. Here, we demonstrate that oral Neu5Ac supplementation preserves intestinal homeostasis in both natural aging and dextran sulfate sodium (DSS)-induced colitis models. Neu5Ac enhanced epithelial barrier integrity, increased tight-junction proteins, and maintained mucosal architecture. It alleviated systemic and local inflammation by suppressing macrophage infiltration and polarization toward the pro-inflammatory phenotype while maintaining tissue-reparative macrophages. Neu5Ac also selectively enriched butyrate-producing bacterial taxa, including Butyricimonas synergistica and Parabacteroides goldsteinii, thereby increasing fecal butyrate levels, without globally altering microbial diversity. Mechanistically, transcriptomic profiling implicated the HIF-1 signaling pathway in mediating the anti-inflammatory effects of Neu5Ac. Consistently, Neu5Ac reduced colonic HIF-1α protein signals, predominantly localized to inflammatory cells, and suppressed HIF-1α expression in LPS-stimulated macrophages. Neu5Ac promoted epithelial regeneration and mitigated senescence-associated p53 activation, thereby restoring gut homeostasis. Importantly, Neu5Ac exhibited excellent biosafety in vivo. Together, these findings identify Neu5Ac as a bioactive nutritional molecule that sustains intestinal homeostasis through coordinated epithelial, immune, and microbial modulation, offering a promising preventive strategy against aging- and inflammation-driven intestinal disorders.

The skin is a three-dimensional organ composed of multilayered tissues, in which the epidermis, dermis, and subcutaneous adipose layer cooperate to maintain protection, thermoregulation, and repair. Although recent advances in tissue-engineered skin substitutes have improved cutaneous regeneration, strategies that simultaneously promote dermal and adipose restoration remain limited. Here, we developed a bi-layered tissue-engineered skin scaffold with dermal-adipose architecture fabricated by conjugate electrospinning of polycaprolactone solutions containing acellular dermal matrix (ADM) or decellularized adipose tissue (DAT). The construct exhibited dual bioactivity: stimulating fibroblast proliferation and collagen remodeling in the dermal layer, while promoting adipose-derived stem cell proliferation and adipogenesis in the adipose layer. In a full-thickness nude rat wound model, the scaffold enhanced vascularization, modulated inflammation, and accelerated regeneration of both dermal and adipose tissues. These findings demonstrate a versatile platform for multilayered skin tissue engineering and provide new insight into dermal-adipose synergistic regeneration.

Despite advancements in bio-manufacturing, the fabrication of large-scale vascularized tissue with heterogeneous cells remains a daunting challenge. To address this challenge, the reverse engineered structured tissue (REST) three-dimensional (3D) bioprinting method was proposed. This strategy enables the seeding and subsequent assembly of multiple tissue-specific constituent cells onto a robust, flexible, 3D biomimetic vascular scaffold with long-term perfusion capability. The material choices for the vessel network and seeding cells could be decoupled, and separate co-culture of multiple seeding cells in a customized bioreactor could be realized. The cellular layers could be reassembled into an engineered tissue by manually folding the robust vessels. Centimeter-scale vascularized skin-flap-like tissues that comprise epidermal, dermal, and adipose layers were engineered with an in vivo-like communicating vascular network using this strategy. The engineered tissue exhibits three-layered cellular heterogeneity (containing HaCaT cells, fibroblasts, and adipose-derived stem cells) and perfusable tubes (containing HUVECs and VSMCs). The complex tissue could be remolded through in vitro perfusion of vessel network and specific culture/differentiation medium supplied to tissue-specific cellular layers. After in vivo transplantation for three months, the tissue construct formed a viable complex tissue with a rich network of blood vessels. Our results demonstrate that "REST" bioprinting technology can be used to fabricate multicellular tissues, ranging from millimeter to centimeter scales with perfusable vessels, opening new avenues for functional artificial organ bioprinting.

Emerging evidence suggests that gut microbiota-derived signals can influence distant organs including the skeleton, yet the key microbial effectors remain elusive. Here, we identify Amuc_1473, a previously uncharacterized protein enriched in extracellular vesicles (EVs) from the commensal bacterium Akkermansia muciniphila (Akk), as a critical mediator of gut-bone communication. Amuc_1473 directly promotes osteogenesis and suppresses osteoclastogenesis by binding to negative elongation factor E (NELF-E) and ribosomal protein L26 (RPL26), regulators of transcriptional pausing and mRNA translation, respectively. Notably, Amuc_1473 levels decline in bone and circulation under diverse pro-osteoporotic conditions-including aging, estrogen deficiency, mechanical unloading, high-fat diet, smoking, alcohol, and chronic stress-paralleling reductions in Akk and its EVs. Intermittent fasting robustly restores Akk abundance, Amuc_1473 levels, and bone quality in these models, via enhanced mucin production. Our findings establish Amuc_1473 as a microbial effector that systemically regulates bone homeostasis, offering a translatable strategy to prevent or treat multifactorial osteoporosis.

Osteoporosis is frequently accompanied by a shift in the fate of bone marrow mesenchymal stromal cells (BMSCs) from osteogenesis toward adipogenesis, contributing to bone-fat imbalance and fragility fractures. Here, we evaluated a naturally occurring eight-amino acid rice bran-derived peptide, RBAP (KHNRGDEF), together with an aptamer-RBAP conjugate designed to improve bone accumulation via a previously identified BMSC-targeting nucleic acid aptamer. In ovariectomized mice, RBAP administered either preventively (early after ovariectomy) or therapeutically (after osteoporotic phenotypes had developed) preserved trabecular microarchitecture, improved mechanical properties, reduced marrow adiposity, and accelerated osteoporotic fracture healing. RBAP also conferred bone-protective effects in models of natural aging and disuse osteoporosis. In vitro, RBAP promoted osteogenic differentiation and suppressed adipogenic differentiation of primary BMSCs without detectably affecting osteoclastogenesis. Proteomic pull-down and functional screening identified eukaryotic translation initiation factor 3 subunit L (eIF3L) as a key RBAP-interacting protein, and genetic suppression of eIF3l attenuated RBAP-induced osteogenesis and blunted its bone protective capacity in vivo. Conjugation of RBAP to the BMSC-targeting aptamer increased BMSC uptake and bone tissue accumulation, thereby enhancing its pro-osteogenic and anti-osteoporotic effects at the same administered dose. Our study identifies RBAP as a bioactive peptide candidate for correcting bone-fat imbalance in osteoporosis and support aptamer conjugation as a modular strategy to improve bone delivery.

Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, yet effective therapies are lacking. Here, we show that alternate-day intermittent fasting (IF1:1) attenuates vitamin D-induced VC in mice, whereas a 5:2 regimen is ineffective. The protective effect of IF1:1 is gut microbiota-dependent, particularly through enrichment of Akkermansia muciniphila (Akk). Microbiota-derived extracellular vesicles (EVs) function as nano-scale mediators that bypass the spatiotemporal constraints of bacterial survival to facilitate long-distance communication with host cells, providing a crucial pathway for downstream mechanistic investigation. Akk-derived EVs (Akk-EVs) are internalized by vascular smooth muscle cells (VSMCs), suppressing osteogenic differentiation and calcification in vitro and in vivo. Proteomic analysis identified B2URF3 as a highly enriched functional protein in Akk-EVs and Akk, which interacts with Aldehyde Dehydrogenase 1 Family Member B1 (ALDH1B1) to inhibit VSMC osteogenic transdifferentiation. Clinically, reduced fecal Akk abundance and lower serum B2URF3 levels were observed in patients with coronary calcification. These findings define a gut-vascular axis by which IF1:1 mitigates VC and nominate Akk-EVs and B2URF3 as potential therapeutic targets and biomarkers.

Background Osteoporosis (OP) has traditionally been regarded as an age-related skeletal disorder characterized by bone loss and increased fracture risk. However, accumulating evidence suggests that OP is not merely a downstream manifestation of aging but may participate in systemic pathophysiological processes that extend beyond the skeleton. Conceptual Framework This review summarizes current evidence on the bidirectional interactions between OP and major aging-related disorders, including Alzheimer’s disease, cardiovascular disease, and metabolic dysfunction. We propose the concept of the “bone–organ axis,” highlighting interconnected pathways mediated by chronic inflammation, endocrine signaling, metabolic regulation, and neurohormonal mechanisms. Within this framework, specific axes—such as the bone–brain and bone–cardiovascular axes—are discussed as representative models of cross-organ communication. Implications Reframing OP as both a consequence and a potential contributor to geriatric multimorbidity provides new perspectives for mechanistic investigation and clinical management. Future priorities include longitudinal studies to clarify causal directionality, identification of early cross-organ biomarkers, and development of integrated intervention strategies targeting shared molecular pathways.

Organoids have emerged as a powerful strategy to recapitulate tissue architecture and function, opening new avenues for regenerative medicine. However, clinical translation is hindered by limited control over the assembly of heterogeneous organoid units and the resulting loss of spatial organization at the tissue scale. In addition, macroscale organoid constructs face diffusion-limited oxygen and nutrient transport, leading to central necrosis. The poor vascular integration can hinder the further development and maturation of the organoids, ultimately preventing functional integration. To address these limitations, we developed Neo-Organoid Visualization and Assembly (NOVA), a living assembly strategy that integrates bioprinting with hydrogel-based bio-adhesive assembly to enable high-throughput modular assembly of bone organoids. Using this strategy, we generate a tissue-scale tubular bone organoid graft formed with in situ unidirectional guided vascularization. This structure enables the spatiotemporal coupling of angiogenesis and osteogenesis, enhances the maturation and function of bone organoids, and holds potential for one-step surgical transplantation with rapid perfusion to repair defects.

Low back pain is a leading cause of global disability, with intervertebral disc degeneration (IVDD) as a primary contributor. Emerging evidence suggests a link between gut microbiota and disc health, yet the underlying mechanisms remain unclear. Through Mendelian randomization and a clinical cohort analysis, we identified a causal inverse relationship between Akkermansia muciniphila (Akk) abundance and IVDD risk, with reduced fecal Akk levels correlating with increased IVDD severity. Akk protected against IVDD in microbiota-depleted mice, and this protection was abolished by pharmacologic inhibition of extracellular vesicle (EV) secretion. Consistently, Akk-derived EVs (Akk-EVs) recapitulated the benefits of Akk across natural aging, tail needle puncture, and bipedal standing mouse models, while control bacterium (Escherichia coli) and its EVs did not. Proteomics and functional validation identified B2UKX5 as a key Akk-EV-enriched effector protein. Furthermore, recombinant B2UKX5 attenuated IVDD in vivo and regulated critical pathways for disc homeostasis, including collagen synthesis, extracellular matrix remodeling, and chromatin silencing, as revealed by transcriptomic profiling of microdissected nucleus pulposus and annulus fibrosus tissues. Analysis of clinical samples further confirmed that Akk-EVs and B2UKX5 levels in circulation and intervertebral disc tissues were negatively correlated with IVDD severity. These findings establish a novel gut-disc axis, highlighting Akk, Akk-EVs, and B2UKX5 as promising therapeutic candidates for IVDD prevention and treatment.

Pathological scarring imposes a substantial global healthcare burden, affecting over 100 million individuals annually with costs exceeding $20 billion. Current therapies yield suboptimal outcomes due to limited efficacy and recurrence. Hydrogel‐based wound dressings have emerged as transformative platforms due to their tunable physicochemical properties, bioactivity, and ability to modulate the wound microenvironment. This review uniquely integrates scar biology with hydrogel‐based therapeutic strategies. A phase‐specific framework that correlates hydrogel functions is provided with key scar‐influencing events, including inflammation regulation, fibroblast reprograming, extracellular matrix remodeling, and skin appendage regeneration. Moreover, cutting‐edge innovations are highlighted such as stimuli‐responsive hydrogels (pH/temperature/light), nanocomposite systems, and 3D‐printed scaffolds that enable spatiotemporal control of drug release and dynamic microenvironment modulation. Furthermore, unresolved clinical translation barriers are critically addressed, including scalability, standardization, biocompatibility, and immune response variability, proposing interdisciplinary solutions. By synthesizing recent advances and persistent limitations, this work provides a translational roadmap for developing next‐generation hydrogels to bridge the gap between benchtop innovation and clinical scar‐free tissue regeneration.