Enzyme-responsive liposomes for controlled drug release.

Compared to other nanovectors, liposomes exhibit unique advantages, such as good biosafety and high drug-loading capacity. However, slow drug release from conventional liposomes makes most payloads unavailable, restricting the therapeutic efficacy. Therefore, in the last ∼20 years, enzyme-responsive liposomes have been extensively investigated, which liberate drugs under the stimulation of enzymes overexpressed at disease sites. In this review, we elaborate on the research progress on enzyme-responsive liposomes. The involved enzymes mainly include phospholipases, particularly phospholipase A2, matrix metalloproteinases, cathepsins, and esterases. These enzymes can cleave ester bonds or specific peptide sequences incorporated in the liposomes for controlled drug release by disrupting the primary structure of liposomes, detaching protective polyethylene glycol shells, or activating liposome-associated prodrugs. Despite decades of efforts, there are still a lack marketed products of enzyme-responsive liposomes. Therefore, more efforts should be made to improve the safety and effectiveness of enzyme-responsive liposomes and address the issues associated with production scale-up.

MMP13-targeted siRNA-loaded micelles for diagnosis and treatment of posttraumatic osteoarthritis.

Posttraumatic osteoarthritis (PTOA) patients are often diagnosed by X-ray imaging at a middle-late stage when drug interventions are less effective. Early PTOA is characterized by overexpressed matrix metalloprotease 13 (MMP13). Herein, we constructed an integrated diagnosis and treatment micelle modified with MMP13 enzyme-detachable, cyanine 5 (Cy5)-containing PEG, black hole quencher-3 (BHQ3), and cRGD ligands and loaded with siRNA silencing MMP13 (siM13), namely ERMs@siM13. ERMs@siM13 could be cleaved by MMP13 in the diseased cartilage tissues to detach the PEG shell, causing cRGD exposure. Accordingly, the ligand exposure promoted micelle uptake by the diseased chondrocytes by binding to cell surface αvß3 integrin, increasing intracellular siM13 delivery for on-demand MMP13 downregulation. Meanwhile, the Cy5 fluorescence was restored by detaching from the BHQ3-containing micelle, precisely reflecting the diseased cartilage state. In particular, the intensity of Cy5 fluorescence generated by ERMs@siM13 that hinged on the MMP13 levels could reflect the PTOA severity, enabling the physicians to adjust the therapeutic regimen. Finally, in the murine PTOA model, ERMs@siM13 could diagnose the early-stage PTOA, perform timely interventions, and monitor the OA progression level during treatment through a real-time detection of MMP13. Therefore, ERMs@siM13 represents an appealing approach for early-stage PTOA theranostics.

Ginsenoside Rh4 prevents endothelial dysfunction as a novel AMPK activator.

BACKGROUND AND PURPOSE: The AMP-activated protein kinase (AMPK) signalling pathway is a desirable target for various cardiovascular diseases (CVD), while the involvement of AMPK-mediated specific downstream pathways and effective interventions in hyperlipidaemia-induced endothelial dysfunction remain largely unknown. Herein, we aim to identify an effective AMPK activator and to explore its efficacy and mechanism against endothelial dysfunction. EXPERIMENTAL APPROACH: Molecular docking technique was adopted to screen for the potent AMPK activator among 11 most common rare ginsenosides. In vivo, poloxamer 407 (P407) was used to induce acute hyperlipidaemia in C57BL/6J mice. In vitro, palmitic acid (PA) was used to induce lipid toxicity in HAEC cells. KEY RESULTS: We discovered the strongest binding of ginsenoside Rh4 to AMPKα1 and confirmed the action of Rh4 on AMPK activation. Rh4 effectively attenuated hyperlipidaemia-related endothelial injury and oxidative stress both in vivo and in vitro and restored cell viability, mitochondrial membrane potential and mitochondrial oxygen consumption rate in HAEC cells. Mechanistically, Rh4 bound to AMPKα1 and simultaneously up-regulated AKT/eNOS-mediated NO release, promoted PGC-1α-mediated mitochondrial biogenesis and inhibited P38 MAPK/NFκB-mediated inflammatory responses in both P407-treated mice and PA-treated HAEC cells. The AMPK inhibitor Compound C treatment completely abrogated the regulation of Rh4 on the above pathways and weakened the lowering effect of Rh4 on endothelial impairment markers, suggesting that the beneficial effects of Rh4 are AMPK dependent. CONCLUSION AND IMPLICATIONS: Rh4 may serve as a novel AMPK activator to protect against hyperlipidaemia-induced endothelial dysfunction, providing new insights into the prevention and treatment of endothelial injury-associated CVD.

Organoid bioinks: construction and application.

Organoids have emerged as crucial platforms in tissue engineering and regenerative medicine but confront challenges in faithfully mimicking native tissue structures and functions. Bioprinting technologies offer a significant advancement, especially when combined with organoid bioinks-engineered formulations designed to encapsulate both the architectural and functional elements of specific tissues. This review provides a rigorous, focused examination of the evolution and impact of organoid bioprinting. It emphasizes the role of organoid bioinks that integrate key cellular components and microenvironmental cues to more accurately replicate native tissue complexity. Furthermore, this review anticipates a transformative landscape invigorated by the integration of artificial intelligence with bioprinting techniques. Such fusion promises to refine organoid bioink formulations and optimize bioprinting parameters, thus catalyzing unprecedented advancements in regenerative medicine. In summary, this review accentuates the pivotal role and transformative potential of organoid bioinks and bioprinting in advancing regenerative therapies, deepening our understanding of organ development, and clarifying disease mechanisms.

Research Progress in Hydrogels for Cartilage Organoids.

The repair and regeneration of cartilage has always been a hot topic in medical research. Cartilage organoids (CORGs) are special cartilage tissue created using tissue engineering techniques outside the body. These engineered organoids tissues provide models that simulate the complex biological functions of cartilage, opening new possibilities for cartilage regenerative medicine and treatment strategies. However, it is crucial to establish suitable matrix scaffolds for the cultivation of CORGs. In recent years, utilizing hydrogel to culture stem cells and induce their differentiation into chondrocytes has emerged as a promising method for the in vitro construction of CORGs. In this review, the methods for establishing CORGs are summarized and an overview of the advantages and limitations of using matrigel in the cultivation of such organoids is provided. Furthermore, the importance of cartilage tissue ECM and alternative hydrogel substitutes for Matrigel, such as alginate, peptides, silk fibroin, and DNA derivatives is discussed, and the pros and cons of using these hydrogels for the cultivation of CORGs are outlined. Finally, the challenges and future directions in hydrogel research for CORGs are discussed. It is hoped that this article provides valuable references for the design and development of hydrogels for CORGs.

Deficiency of Cbfß in articular cartilage leads to osteoarthritis-like phenotype through Hippo/Yap, TGFß, and Wnt/ß-catenin signaling pathways.

Osteoarthritis (OA) is the most prevalent degenerative joint disorder, causing physical impairments among the elderly. Core binding factor subunit ß (Cbfß) has a critical role in bone homeostasis and cartilage development. However, the function and mechanism of Cbfß in articular cartilage and OA remains unclear. We found that Cbfßf/fAggrecan-CreERT mice with Cbfß-deficiency in articular cartilage developed a spontaneous osteoarthritis-like phenotype with articular cartilage degradation. Immunofluorescence staining showed that Cbfßf/fAggrecan-CreERT mice exhibited a significant increase in the expression of articular cartilage degradation markers and inflammatory markers in the knee joints. RNA-sequencing analysis demonstrated that Cbfß orchestrated Hippo/Yap, TGFß/Smad, and Wnt/ß-catenin signaling pathways in articular cartilage, and Cbfß deficiency resulted in the abnormal expression of downstream genes involved in maintaining articular cartilage homeostasis. Immunofluorescence staining results showed Cbfß deficiency significantly increased active ß-catenin and TCF4 expression while reducing Yap, TGFß1, and p-Smad 2/3 expression. Western blot and qPCR validated gene expression changes in hip articular cartilage of Cbfß-deficient mice. Our results demonstrate that deficiency of Cbfß in articular cartilage leads to an OA-like phenotype via affecting Hippo/Yap, TGFß, and Wnt/ß-catenin signaling pathways, disrupting articular cartilage homeostasis and leading to the pathological process of OA in mice. Our results indicate that targeting Cbfß may be a potential therapeutic target for the design of novel and effective treatments for OA.

Engineering Large-Scale Self-Mineralizing Bone Organoids with Bone Matrix-Inspired Hydroxyapatite Hybrid Bioinks.

Addressing large bone defects remains a significant challenge owing to the inherent limitations in self-healing capabilities, resulting in prolonged recovery and suboptimal regeneration. Although current clinical solutions are available, they have notable shortcomings, necessitating more efficacious approaches to bone regeneration. Organoids derived from stem cells show great potential in this field; however, the development of bone organoids has been hindered by specific demands, including the need for robust mechanical support provided by scaffolds and hybrid extracellular matrices (ECM). In this context, bioprinting technologies have emerged as powerful means of replicating the complex architecture of bone tissue. The research focused on the fabrication of a highly intricate bone ECM analog using a novel bioink composed of gelatin methacrylate/alginate methacrylate/hydroxyapatite (GelMA/AlgMA/HAP). Bioprinted scaffolds facilitate the long-term cultivation and progressive maturation of extensive bioprinted bone organoids, foster multicellular differentiation, and offer valuable insights into the initial stages of bone formation. The intrinsic self-mineralizing quality of the bioink closely emulates the properties of natural bone, empowering organoids with enhanced bone repair for both in vitro and in vivo applications. This trailblazing investigation propels the field of bone tissue engineering and holds significant promise for its translation into practical applications.

Cyaonoside A-loaded composite hydrogel microspheres to treat osteoarthritis by relieving chondrocyte inflammation.

Cyaonoside A (CyA), derived from the natural Chinese medicine, Cyathula officinalis Kuan, which was for a long time used to treat knee injuries and relieve joint pain in traditional Chinese medicine, showed an unclear mechanism for protecting cartilage. In addition, CyA was poorly hydrosoluble and incapable of being injected directly into the joint cavity, which limited its clinical application. This study reveals that CyA resisted IL-1ß-mediated chondrogenic inflammation and apoptosis. Next, transcriptome sequencing is used to explore the potential mechanisms underlying CyA regulation of MSC chondrogenic differentiation. Based on these findings, CyA-loaded composite hydrogel microspheres (HLC) were developed and they possessed satisfactory loading efficiency, a suitable degradation rate and good biocompatibility. HLC increased chondrogenic anabolic gene (Acan, COL2A, and SOX9) expression, while downregulating the expression of the catabolic marker MMP13 in vitro. In the osteoarthritis mouse model, HLC demonstrated promising therapeutic capabilities by protecting the integrity of articular cartilage. In conclusion, this study provides insights into the regulatory mechanisms of CyA for chondrocytes and proposes a composite hydrogel microsphere-based advanced therapeutic strategy for osteoarthritis.

Synthetic biology-based bacterial extracellular vesicles displaying BMP-2 and CXCR4 to ameliorate osteoporosis.

Osteoporosis (OP) is a systematic bone disease characterized by low bone mass and fragile bone microarchitecture. Conventional treatment for OP has limited efficacy and long-term toxicity. Synthetic biology makes bacterial extracellular vesicle (BEVs)-based therapeutic strategies a promising alternative for the treatment of OP. Here, we constructed a recombinant probiotics Escherichia coli Nissle 1917-pET28a-ClyA-BMP-2-CXCR4 (ECN-pClyA-BMP-2-CXCR4), in which BMP-2 and CXCR4 were overexpressed in fusion with BEVs surface protein ClyA. Subsequently, we isolated engineered BEVs-BMP-2-CXCR4 (BEVs-BC) for OP therapy. The engineered BEVs-BC exhibited great bone targeting in vivo. In addition, BEVs-BC had good biocompatibility and remarkable ability to promote osteogenic differentiation of BMSCs. Finally, the synthetic biology-based BEVs-BC significantly prevented the OP in an ovariectomized (OVX) mouse model. In conclusion, we constructed BEVs-BC with both bone-targeting and bone-forming in one-step using synthetic biology, which provides an effective strategy for OP and has great potential for industrialization.

Smart osteoclasts targeted nanomedicine based on amorphous CaCO3 for effective osteoporosis reversal.

BACKGROUND: Osteoporosis is characterized by an imbalance in bone homeostasis, resulting in the excessive dissolution of bone minerals due to the acidified microenvironment mediated by overactive osteoclasts. Oroxylin A (ORO), a natural flavonoid, has shown potential in reversing osteoporosis by inhibiting osteoclast-mediated bone resorption. The limited water solubility and lack of targeting specificity hinder the effective accumulation of Oroxylin A within the pathological environment of osteoporosis. RESULTS: Osteoclasts' microenvironment-responsive nanoparticles are prepared by incorporating Oroxylin A with amorphous calcium carbonate (ACC) and coated with glutamic acid hexapeptide-modified phospholipids, aiming at reinforcing the drug delivery efficiency as well as therapeutic effect. The obtained smart nanoparticles, coined as OAPLG, could instantly neutralize acid and release Oroxylin A in the extracellular microenvironment of osteoclasts. The combination of Oroxylin A and ACC synergistically inhibits osteoclast formation and activity, leading to a significant reversal of systemic bone loss in the ovariectomized mice model. CONCLUSION: The work highlights an intelligent nanoplatform based on ACC for spatiotemporally controlled release of lipophilic drugs, and illustrates prominent therapeutic promise against osteoporosis.

Expert consensus on Prospective Precision Diagnosis and Treatment Strategies for Osteoporotic Fractures.

Osteoporotic fractures are the most severe complications of osteoporosis, characterized by poor bone quality, difficult realignment and fixation, slow fracture healing, and a high risk of recurrence. Clinically managing these fractures is relatively challenging, and in the context of rapid aging, they pose significant social hazards. The rapid advancement of disciplines such as biophysics and biochemistry brings new opportunities for future medical diagnosis and treatment. However, there has been limited attention to precision diagnosis and treatment strategies for osteoporotic fractures both domestically and internationally. In response to this, the Chinese Medical Association Orthopaedic Branch Youth Osteoporosis Group, Chinese Geriatrics Society Geriatric Orthopaedics Committee, Chinese Medical Doctor Association Orthopaedic Physicians Branch Youth Committee Osteoporosis Group, and Shanghai Association of Integrated Traditional Chinese and Western Medicine Osteoporosis Professional Committee have collaborated to develop this consensus. It aims to elucidate emerging technologies that may play a pivotal role in both diagnosis and treatment, advocating for clinicians to embrace interdisciplinary approaches and incorporate these new technologies into their practice. Ultimately, the goal is to improve the prognosis and quality of life for elderly patients with osteoporotic fractures.

AI energized hydrogel design, optimization and application in biomedicine.

Traditional hydrogel design and optimization methods usually rely on repeated experiments, which is time-consuming and expensive, resulting in a slow-moving of advanced hydrogel development. With the rapid development of artificial intelligence (AI) technology and increasing material data, AI-energized design and optimization of hydrogels for biomedical applications has emerged as a revolutionary breakthrough in materials science. This review begins by outlining the history of AI and the potential advantages of using AI in the design and optimization of hydrogels, such as prediction and optimization of properties, multi-attribute optimization, high-throughput screening, automated material discovery, optimizing experimental design, and etc. Then, we focus on the various applications of hydrogels supported by AI technology in biomedicine, including drug delivery, bio-inks for advanced manufacturing, tissue repair, and biosensors, so as to provide a clear and comprehensive understanding of researchers in this field. Finally, we discuss the future directions and prospects, and provide a new perspective for the research and development of novel hydrogel materials for biomedical applications.

[Expert consensus on integrated traditional Chinese and western medicine diagnosis and treatment for osteoporotic fractures].

Osteoporotic fractures represent the most severe complications of osteoporosis,characterized by insidious onset,high mortality and disability rates,and a steadily increasing incidence,imposing a significant socioeconomic burden. Western medicine has advantages in diagnosis and surgical interventions,while traditional Chinese medicine excels in holistic management and the restoration of bodily equilibrium. The integration of both traditional Chinese medicine (TCM) and western medicine emerges as an effective therapeutic strategy for osteoporotic fractures. In order to propagate the concept of integrated diagnosis and treatment,foster the advancement of integrated medical techniques for osteoporotic fractures,and establish standardized and normative protocols for disease prevention,diagnosis,and treatment,a consensus expert group,led by Geriatric Branch of Chinese Geriatrics Society,the Young Osteoporosis Group of Orthopedics Branch of Chinese Medical Association,Osteoporosis Group of Orthopedics Branch of Chinese Physician Association,and Osteoporosis Professional Committee of the Shanghai Society of Integrated Traditional Chinese and Western Medicine,was established. This group engaged in deliberations and formulated the "Expert Consensus on Integrated Traditional Chinese and Western Medicine Diagnosis and Treatment of Osteoporotic Fractures" elucidating the concept of integrated medicine and offering recommendations in the domains of prevention,diagnosis,and treatment,with the aspiration of ameliorating the prognosis of osteoporotic fractures and enhancing the quality of life for these patients.

Boosting cartilage repair with silk fibroin-DNA hydrogel-based cartilage organoid precursor.

Osteoarthritis (OA), a common degenerative disease, is characterized by high disability and imposes substantial economic impacts on individuals and society. Current clinical treatments remain inadequate for effectively managing OA. Organoids, miniature 3D tissue structures from directed differentiation of stem or progenitor cells, mimic native organ structures and functions. They are useful for drug testing and serve as active grafts for organ repair. However, organoid construction requires extracellular matrix-like 3D scaffolds for cellular growth. Hydrogel microspheres, with tunable physical and chemical properties, show promise in cartilage tissue engineering by replicating the natural microenvironment. Building on prior work on SF-DNA dual-network hydrogels for cartilage regeneration, we developed a novel RGD-SF-DNA hydrogel microsphere (RSD-MS) via a microfluidic system by integrating photopolymerization with self-assembly techniques and then modified with Pep-RGDfKA. The RSD-MSs exhibited uniform size, porous surface, and optimal swelling and degradation properties. In vitro studies demonstrated that RSD-MSs enhanced bone marrow mesenchymal stem cells (BMSCs) proliferation, adhesion, and chondrogenic differentiation. Transcriptomic analysis showed RSD-MSs induced chondrogenesis mainly through integrin-mediated adhesion pathways and glycosaminoglycan biosynthesis. Moreover, in vivo studies showed that seeding BMSCs onto RSD-MSs to create cartilage organoid precursors (COPs) significantly enhanced cartilage regeneration. In conclusion, RSD-MS was an ideal candidate for the construction and long-term cultivation of cartilage organoids, offering an innovative strategy and material choice for cartilage regeneration and tissue engineering.

Heterogeneous DNA hydrogel loaded with Apt02 modified tetrahedral framework nucleic acid accelerated critical-size bone defect repair.

Segmental bone defects, stemming from trauma, infection, and tumors, pose formidable clinical challenges. Traditional bone repair materials, such as autologous and allogeneic bone grafts, grapple with limitations including source scarcity and immune rejection risks. The advent of nucleic acid nanotechnology, particularly the use of DNA hydrogels in tissue engineering, presents a promising solution, attributed to their biocompatibility, biodegradability, and programmability. However, these hydrogels, typically hindered by high gelation temperatures (∼46 °C) and high construction costs, limit cell encapsulation and broader application. Our research introduces a novel polymer-modified DNA hydrogel, developed using nucleic acid nanotechnology, which gels at a more biocompatible temperature of 37 °C and is cost-effective. This hydrogel then incorporates tetrahedral Framework Nucleic Acid (tFNA) to enhance osteogenic mineralization. Furthermore, considering the modifiability of tFNA, we modified its chains with Aptamer02 (Apt02), an aptamer known to foster angiogenesis. This dual approach significantly accelerates osteogenic differentiation in bone marrow stromal cells (BMSCs) and angiogenesis in human umbilical vein endothelial cells (HUVECs), with cell sequencing confirming their targeting efficacy, respectively. In vivo experiments in rats with critical-size cranial bone defects demonstrate their effectiveness in enhancing new bone formation. This innovation not only offers a viable solution for repairing segmental bone defects but also opens avenues for future advancements in bone organoids construction, marking a significant advancement in tissue engineering and regenerative medicine.

Lipid nanovehicles overcome barriers to systemic RNA delivery: Lipid components, fabrication methods, and rational design.

Lipid nanovehicles are currently the most advanced vehicles used for RNA delivery, as demonstrated by the approval of patisiran for amyloidosis therapy in 2018. To illuminate the unique superiority of lipid nanovehicles in RNA delivery, in this review, we first introduce various RNA therapeutics, describe systemic delivery barriers, and explain the lipid components and methods used for lipid nanovehicle preparation. Then, we emphasize crucial advances in lipid nanovehicle design for overcoming barriers to systemic RNA delivery. Finally, the current status and challenges of lipid nanovehicle-based RNA therapeutics in clinical applications are also discussed. Our objective is to provide a comprehensive overview showing how to utilize lipid nanovehicles to overcome multiple barriers to systemic RNA delivery, inspiring the development of more high-performance RNA lipid nanovesicles in the future.

Articular cartilage repair biomaterials: strategies and applications.

Articular cartilage injury is a frequent worldwide disease, while effective treatment is urgently needed. Due to lack of blood vessels and nerves, the ability of cartilage to self-repair is limited. Despite the availability of various clinical treatments, unfavorable prognoses and complications remain prevalent. However, the advent of tissue engineering and regenerative medicine has generated considerable interests in using biomaterials for articular cartilage repair. Nevertheless, there remains a notable scarcity of comprehensive reviews that provide an in-depth exploration of the various strategies and applications. Herein, we present an overview of the primary biomaterials and bioactive substances from the tissue engineering perspective to repair articular cartilage. The strategies include regeneration, substitution, and immunization. We comprehensively delineate the influence of mechanically supportive scaffolds on cellular behavior, shedding light on emerging scaffold technologies, including stimuli-responsive smart scaffolds, 3D-printed scaffolds, and cartilage bionic scaffolds. Biologically active substances, including bioactive factors, stem cells, extracellular vesicles (EVs), and cartilage organoids, are elucidated for their roles in regulating the activity of chondrocytes. Furthermore, the composite bioactive scaffolds produced industrially to put into clinical use, are also explicitly presented. This review offers innovative solutions for treating articular cartilage ailments and emphasizes the potential of biomaterials for articular cartilage repair in clinical translation.

A Factor-Free Hydrogel with ROS Scavenging and Responsive Degradation for Enhanced Diabetic Bone Healing.

In view of the increased levels of reactive oxygen species (ROS) that disturb the osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), the repair of diabetic bone defects remains a great challenge. Herein, a factor-free hydrogel is reported with ROS scavenging and responsive degradation properties for enhanced diabetic bone healing. These hydrogels contain ROS-cleavable thioketal (TK) linkers and ultraviolet (UV)-responsive norbornene (NB) groups conjugated with 8-arm PEG macromers, which are formed via UV crosslinking-mediated gelation. Upon reacting with high levels of ROS in the bone defect microenvironment, ROS-cleavable TK linkers are destroyed, allowing the responsive degradation of hydrogels, which promotes the migration of BMSCs. Moreover, ROS levels are reduced through hydrogel-mediated ROS scavenging to reverse BMSC differentiation from adipogenic to osteogenic phenotype. As such, a favorable microenvironment is created after simultaneous ROS scavenging and hydrogel degradation, leading to the effective repair of bone defects in diabetic mouse models, even without the addition of growth factors. Thus, this study presents a responsive hydrogel platform that regulates ROS scavenging and stromal degradation in bone engineering.

Diets intervene osteoporosis via gut-bone axis.

Osteoporosis is a systemic skeletal disease that seriously endangers the health of middle-aged and older adults. Recently, with the continuous deepening of research, an increasing number of studies have revealed gut microbiota as a potential target for osteoporosis, and the research concept of the gut-bone axis has gradually emerged. Additionally, the intake of dietary nutrients and the adoption of dietary patterns may affect the gut microbiota, and alterations in the gut microbiota might also influence the metabolic status of the host, thus adjusting bone metabolism. Based on the gut-bone axis, dietary intake can also participate in the modulation of bone metabolism by altering abundance, diversity, and composition of gut microbiota. Herein, combined with emerging literatures and relevant studies, this review is aimed to summarize the impacts of different dietary components and patterns on osteoporosis by acting on gut microbiota, as well as underlying mechanisms and proper dietary recommendations.

Extracellular derivatives for bone metabolism.

BACKGROUND: Bone metabolism can maintain the normal homeostasis and function of bone tissue. Once the bone metabolism balance is broken, it will cause osteoporosis, osteoarthritis, bone defects, bone tumors, or other bone diseases. However, such orthopedic diseases still have many limitations in clinical treatment, such as drug restrictions, drug tolerance, drug side effects, and implant rejection. AIM OF REVIEW: In complex bone therapy and bone regeneration, extracellular derivatives have become a promising research focus to solve the problems of bone metabolic diseases. These derivatives, which include components such as extracellular matrix, growth factors, and extracellular vesicles, have significant therapeutic potential. It has the advantages of good biocompatibility, low immune response, and dynamic demand for bone tissue. The purpose of this review is to provide a comprehensive perspective on extracellular derivatives for bone metabolism and elucidate the intrinsic properties and versatility of extracellular derivatives. Further discussion of them as innovative advanced orthopedic materials for improving the effectiveness of bone therapy and regeneration processes. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, we first listed the types and functions of three extracellular derivatives. Then, we discussed the effects of extracellular derivatives of different cell sources on bone metabolism. Subsequently, we collected applications of extracellular derivatives in the treatment of bone metabolic diseases and summarized the advantages and challenges of extracellular derivatives in clinical applications. Finally, we prospected the extracellular derivatives in novel orthopedic materials and clinical applications. We hope that the comprehensive understanding of extracellular derivatives in bone metabolism will provide new solutions to bone diseases.