JOURNAL/nrgr/04.03/01300535-202512000-00028/figure1/v/2025-01-31T122243Z/r/image-tiff Adipose-derived stem cell, one type of mesenchymal stem cells, is a promising approach in treating ischemia-reperfusion injury caused by occlusion of the middle cerebral artery. However, its application has been limited by the complexities of the ischemic microenvironment. Hydrogel scaffolds, which are composed of hyaluronic acid and chitosan, exhibit excellent biocompatibility and biodegradability, making them promising candidates as cell carriers. Vascular endothelial growth factor is a crucial regulatory factor for stem cells. Both hyaluronic acid and chitosan have the potential to make the microenvironment more hospitable to transplanted stem cells, thereby enhancing the therapeutic effect of mesenchymal stem cell transplantation in the context of stroke. Here, we found that vascular endothelial growth factor significantly improved the activity and paracrine function of adipose-derived stem cells. Subsequently, we developed a chitosan-hyaluronic acid hydrogel scaffold that incorporated vascular endothelial growth factor and first injected the scaffold into an animal model of cerebral ischemia-reperfusion injury. When loaded with adipose-derived stem cells, this vascular endothelial growth factor-loaded scaffold markedly reduced neuronal apoptosis caused by oxygen-glucose deprivation/reoxygenation and substantially restored mitochondrial membrane potential and axon morphology. Further in vivo experiments revealed that this vascular endothelial growth factor-loaded hydrogel scaffold facilitated the transplantation of adipose-derived stem cells, leading to a reduction in infarct volume and neuronal apoptosis in a rat model of stroke induced by transient middle cerebral artery occlusion. It also helped maintain mitochondrial integrity and axonal morphology, greatly improving rat motor function and angiogenesis. Therefore, utilizing a hydrogel scaffold loaded with vascular endothelial growth factor as a stem cell delivery system can mitigate the adverse effects of ischemic microenvironment on transplanted stem cells and enhance the therapeutic effect of stem cells in the context of stroke.

Osteoarthritis (OA), a degenerative joint disease, is characterized by chondrocyte senescence, extracellular matrix (ECM) degradation, and chronic inflammation, with limited regenerative capacity. Current therapies primarily provide symptom relief, therefore highlighting the need for more effective strategies to address OA's multifactorial pathology. This study introduces an innovative selenium nanozyme-crosslinked injectable composite hydrogel (Se/PRP-OGel), which combines selenium nanoparticles (SeNPs) with platelet-rich plasma (PRP) in a biocompatible oxidized chondroitin sulfate-gelatin scaffold (OGel), to address OA through an integrated "outside-in" and "inside-out" strategy. The "outside-in" strategy utilizes SeNPs to scavenge reactive oxygen species (ROS), alleviate oxidative stress, and restore redox balance, thereby reducing extracellular damage and modulating inflammation in the OA microenvironment. Concurrently, the "inside-out" strategy utilizes PRP's bioactive growth factors (e.g., TGF-β, IGF, FGF) to rejuvenate senescent chondrocytes, stimulate proliferation, and enhance ECM synthesis, creating a regenerative microenvironment. The results showed that Se/PRP-OGel demonstrated excellent biocompatibility, reduced ROS levels, mitigated chondrocyte senescence, and balanced ECM homeostasis. Moreover, it promoted cartilage repair, pain relief, and functional restoration in an OA rat model. This dual approach interrupts OA's degenerative cycle and fosters cartilage regeneration, providing a groundbreaking solution for effective cartilage regeneration and OA treatment.

Nucleic acid drugs represent the latest generation of precision therapeutics, holding significant promise for the treatment of a wide range of intractable diseases. Delivery technology is crucial for the clinical application of nucleic acid drugs. However, extrahepatic delivery of nucleic acid drugs remains a significant challenge. Systemic administration often fails to achieve sufficient drug enrichment in target tissues. Localized administration has emerged as the predominant approach to facilitate extrahepatic delivery. While localized administration can significantly enhance drug accumulation at the injection sites, nucleic acid drugs still face biological barriers in reaching the target lesions. This review focuses on non-viral nucleic acid drug delivery techniques utilized in local administration for the treatment of extrahepatic diseases. First, the classification of nucleic acid drugs is described. Second, the current major non-viral delivery technologies for nucleic acid drugs are discussed. Third, the bio-barriers, administration approaches, and recent research advances in the local delivery of nucleic acid drugs for treating lung, brain, eye, skin, joint, and heart-related diseases are highlighted. Finally, the challenges associated with the localized therapeutic application of nucleic acid drugs are addressed.

Endocrine therapy resistance (ETR) in breast cancer (BC) is a multicausal phenomenon with diverse alterations in the tumor cell interactome. Within these alterations, non-coding RNAs (ncRNAs) such as micro-RNAs (miRNAs) modulate the expression of tumor suppressor genes and proto-oncogenes, such as the ESR1 gene encoding estrogen receptor alpha (ERα). This work aims to review the effects of miRNAs targeting ERα mRNA and their mechanisms related to ETR in BC. A thorough review of the literature and an in silico study were carried out to elucidate the involvement of each miRNA, thus contributing to the understanding of ETR in BC.

Osteoarthritis (OA) is the most common joint disease characterized by disruption of extracellular matrix (ECM) homeostasis, chronic inflammation, and upregulation of senescent phenotypes. Ginsenoside Rh1 (Rh1) exerted various pharmacological activities, including anti-inflammatory, anti-cancer, and neuroprotective effects. Herein, we aimed to explore the role and mechanism of Rh1 in OA. In IL-1β-induced OA chondrocytes, Rh1 alleviated the imbalance of ECM and senescence phenotypes. Furthermore, we found that Rh1 mitigated mitochondrial damage and the impaired mitophagy of chondrocytes induced by IL-1β, and these effects could be prevented by Mdivi-1 (a mitophagy inhibitor). Knockdown of PINK1 or Parkin partially abolished Rh1-mediated chondroprotection, indicating that Rh1 exerts its therapeutic effects via PINK1/Parkin-dependent mitophagy. Based on molecular docking, Compound C (an AMPK inhibitor), and AMPK siRNA, we found that Rh1 regulated PINK1/Parkin-mediated mitophagy through AMPK. Besides, Rh1 alleviated OA by promoting AMPK-mediated mitophagy in the anterior cruciate ligament transection (ACLT) rats. In conclusion, Rh1 alleviated OA progress by regulating AMPK/PINK1/Parkin-mediated mitophagy and is a potentially effective therapeutic target for age-related OA.

Dysregulation of extracellular matrix (ECM) homeostasis plays a pivotal role in the accelerated degradation of cartilage, presenting a notable challenge for effective osteoarthritis (OA) treatment and cartilage regeneration. In this study, we introduced an injectable hydrogel based on streamlined-zinc oxide (ZnO), which is responsive to matrix metallopeptidase (MMP), for the delivery of miR-17-5p. This approach aimed to address cartilage damage by regulating ECM homeostasis. The ZnO/miR-17-5p composite functions by releasing zinc ions to attract native bone marrow mesenchymal stem cells, thereby fostering ECM synthesis through the proliferation of new chondrocytes. Concurrently, sustained delivery of miR-17-5p targets enzymes responsible for matrix degradation, thereby mitigating the catabolic process. Notably, the unique structure of the streamlined ZnO nanoparticles is distinct from their conventional spherical counterparts, which not only optimizes the rheological and mechanical properties of the hydrogels, but also enhances the efficiency of miR-17-5p transfection. Our male rat model demonstrated that the combination of streamlined ZnO, MMP-responsive hydrogels, and miRNA-based therapy effectively managed the equilibrium between catabolism and anabolism within the ECM, presenting a fresh perspective in the realm of OA treatment.

Self-repair of articular cartilage defects is a significant challenge that can be addressed using drug-infused hydrogels, which improve injection convenience and provide immediate in situ adhesion. In this study, we developed a hydrogel incorporating Lipo@Kartogenin (KGN) and the cationic functional peptide SKPPGTSS (SKP) linked to aldehyde-based methacrylated hyaluronic acid (AHAMA). The innovative injectable hydrogel responded to visible light, allowing cross-linking under white light (∼30 s) and effective adhesion to cartilage tissue. The hydrogel facilitated the sustained release of KGN and SKP over approximately 28 days as it degraded, thereby promoting the homing and differentiation of endogenous bone marrow-derived mesenchymal stem cells (BMSCs). Transcriptome sequencing showed that Smad4 expression and activation of the TGF-β signaling pathway are fundamental to these processes. In vivo studies in Sprague-Dawley (SD) rats showed that this hydrogel supports optimal hyaline cartilage regeneration within 8 weeks. In conclusion, our visible light-responsive adhesive co-delivery hydrogel effectively recruited native BMSCs to cartilage lesion sites and provided an environment conducive to their differentiation into cartilage, thereby facilitating effective cartilage regeneration. This innovation represents a novel approach to the clinical repair of cartilage defects.

Osteoarthritis (OA) represents a globally prevalent degenerative bone diseases and is the primary contributors to pain and disability among middle-aged and elderly people, thereby imposing significant social and economic burdens. When articular cartilage is in the aging environment, epigenetic modifications, DNA damage and mitochondrial dysfunction lead to cell senescence. Chondrocyte senescence has been identified as a pivotal event in this metabolic dysregulation of the extracellular matrix (ECM). It can affect the composition and structure of ECM, and the mechanical and biological signals transmitted by ECM to senescent chondrocytes affect their physiology and pathology. Over the past few decades, the role of ECM in aging-related OA has received increasing attention. In this review, we summarize the changes of cartilage's major ECM (type II collagen and aggrecan) and the interaction between aging and ECM in OA, and explore therapeutic strategies targeting cartilagae ECM, such as noncoding RNAs, small-molecule drugs, and mesenchymal stem cell (MSC)-derived extracellular vesicles for OA. The aim of this study was to elucidate the potential benefits of ECM-based therapies as novel strategies for the management of OA diseases.

Excessive inflammation, overexpressed reactive oxygen species (ROS), degradation of the extracellular matrix, and high friction aggravate osteoarthritis (OA). Intra-articular injection for local drug delivery in the joint cavity enhances drug retention duration for OA treatment. Nevertheless, it remains a challenge to attenuate OA by thoroughly modulating the joint microenvironment, achieving controlled drug release, and enhancing lubrication. This study develops hyaluronic acid (HA) composite hydrogels, infused with gelatin microspheres containing a drug, utilizing dynamic interactions between phenylboronic acid and catechol to modulate the microenvironment by scavenging ROS, facilitating controlled drug release, and improving lubrication to mitigate OA. The composite hydrogels can be injected by intra-articular injection due to the shear-thinning properties, demonstrating broad ROS scavenging capacity and matrix metalloproteinase-9 responsive drug release. Both the in vitro and in vivo experiments prove the protective efficacy of the composite hydrogels against the degradation of cartilage matrix. Additionally, the hydrogels can offer efficient lubrication and effectively attenuate OA. Thus, the injectable HA composite hydrogels demonstrated potential in the management of OA.

The osteogenic microenvironment (OME) significantly influences bone repair; however, reproducing its dynamic activation and repair processes remains challenging. In this study, we designed injectable porous microspheres modified with composite peptides to investigate cascade alterations in OME and their underlying mechanisms. Poly l-lactic acid microfluidic microspheres underwent surface modifications through alkaline hydrolysis treatment, involving heterogeneous grafting of bovine serum albumin nanoparticles with stem cell-homing peptides (BNP@SKP) and BMP-2 mimicking peptides (P24), respectively. These modifications well-organized the actions of initial release and subsequent in situ grafting of peptides. Cellular experiments demonstrated varied degrees of chemotactic recruitment and osteogenic differentiation in mesenchymal stem cells. Further biological analysis revealed that BNP@SKP targeted the Ras/Erk axis and upregulated matrix metalloproteinase (MMP)2 and MMP9 expression, thereby enhancing initial chemotaxis and recruitment. In vivo studies validated the establishment of a dynamically regulated OME centered on the microspheres, resulting in increased stem cell recruitment, sequential activation of the differentiation microenvironment, and facilitation of in situ osteogenesis without ectopic ossification. In conclusion, this study successfully fabricated composite peptide-modified microspheres and systematically explored the mechanisms of bone formation through sequential activation of OME via heterogeneous grafting of signaling molecules. This provides theoretical evidence for biomaterials based on microenvironment regulation.

Gene therapy offers an ideal potential treatment strategy for osteoarthritis (OA). However, the safe and efficient delivery of therapeutic genes remains highly challenging because of the inactivation in direct delivery of miRNA, low transfection efficiency, and a short half-life. This study introduced a gene therapy strategy using mesenchymal stem cells (MSCs) as a gene delivery platform and achieved the sustained delivery of therapeutic genes via engineered MSCs-derived extracellular vesicles (EVs). The miRNA-874-3p is combined with an exosome-targeting motif and transfected into bone marrow mesenchymal stem cells (BMSCs). The BMSCsmotif+miR874 are then seeded onto hydrogel microspheres, creating the BMSCmotif+miR874/MS system for OA treatment. In vitro experiments demonstrated that miRNA-874-3p not only alleviated inflammation and oxidative stress-induced damage to chondrocytes by downregulating the NF-κB signaling pathway, thereby rejuvenating chondrocytes, but also promoted chondrogenesis in the inflammatory microenvironment. Furthermore, the engineered BMSCs in the system demonstrated prolonged retention in vivo, thereby enabling the sustained delivery of the therapeutic gene, miRNA-874-3p, over an extended duration. In the rat OA model, BMSCmotif+miR874/MS successfully delivered miRNA-874-3p to the articular cartilage and effectively alleviated cartilage degeneration. In conclusion, this EVs-mediated therapeutic gene delivery approach enables miRNA-based gene therapy a viable alternative to surgery for OA treatment and provides a novel option for gene therapy.

Uveitis, a frequently recurrent inflammatory condition of the uvea, poses a significant risk of visual impairment and blindness, primarily due to the excessive generation of reactive oxygen species (ROS) and the activation of signaling pathways that propagate inflammatory responses. Despite the widespread use of corticosteroid eye drops as a standard treatment, these therapies are hindered by limited efficacy, adverse side effects, and poor ocular bioavailability. To address these challenges, polyethyleneimine (PEI)-modified polydopamine (PDA) carrying microRNA-132-3p (miR-132), namely PEI/PDA@miR-132, was developed to simultaneously neutralize ROS and attenuate inflammation in experimental models of acute and chronic uveitis. Mechanistically, PEI/PDA@miR-132 demonstrated remarkable efficacy by suppressing ROS production, inhibiting the pro-inflammatory polarization of macrophages, and downregulating the IκBα/nuclear factor-kappa B (NF-κB) p65 signaling pathway. These effects culminated in the reduction of pro-inflammatory cytokines and mitigation of apoptosis. Therapeutically, PEI/PDA@miR-132 provided significant relief from hallmark symptoms of uveitis, including iris congestion, inflammatory exudation, and retinal folds, while exhibiting superior retinal safety compared to commercially available dexamethasone. Furthermore, it showcased excellent biocompatibility, positioning it as a promising therapeutic strategy for managing oxidative stress- and inflammation-driven diseases such as acute and chronic uveitis.

Osteoarthritis (OA) is a widely encountered degenerative joint disorder marked by gradual cartilage deterioration, inflammation, and pain, which collectively impose considerable strain on global healthcare systems. While traditional therapies typically offer relief from symptoms, they do not tackle the core pathophysiological aspects of the disease. Regenerative medicine has recently risen as a promising field for addressing OA, capitalizing on the regenerative capabilities of stem cells and growth factors to foster tissue healing and renewal. This thorough review delves into the most recent progress in stem cell and growth factor treatments for OA, covering preclinical studies, clinical trials, and novel technological developments. We discuss the diverse origins of stem cells, such as mesenchymal stem cells (MSCs), induced pluripotent stem cells (iPSCs), and adipose-derived stem cells (ASCs), underscoring their therapeutic actions and effectiveness in both preclinical and clinical environments. Moreover, we explore contributions of growth factors like transforming growth factor (TGF)-β, platelet-derived growth factor (PDGF), and insulin-like growth factor (IGF) in modifying OA's pathology and enhancing tissue restoration. Additionally, this review discusses the hurdles and constraints tied to current regenerative strategies, including the standardization of cell sources, the refinement of delivery techniques, and considerations for long-term safety. By meticulously assessing the latest research outcomes and technological breakthroughs, this review aims to shed light on the potential of stem cell and growth factor therapies as forthcoming therapeutic options for OA, thereby propelling forward the domain of regenerative medicine and enhancing clinical results for individuals afflicted with this incapacitating ailment.

Osteoarthritis (OA) is a common and incurable disease in humans and animals. To gain a better understanding of the pathogenesis and identify potential treatments, miRNAs will be extracted and analysed from extracellular vesicles (EVs) of equine adipose derived mesenchymal stem cells (AdMSCs).

For this purpose we cultivated and pretreated AdMSCs under different conditions: interleukin 1β, shock wave, chondrogenic differentiation, chondrogenic differentiation under hypoxia, or after senescence. After treatment, EVs were harvested from the cell culture supernatants. Next-generation sequencing (NGS) was used to sequence the miRNAs from the EVs.

A total of 89 miRNAs whose expression was significantly altered compared with that of an untreated negative control were identified. On average, 53 miRNAs were upregulated and 6 miRNAs were downregulated. Among others, the miRNAs eca-miR-101, eca-miR-143, eca-miR-145, eca-miR-146a, eca-miR-27a, eca-miR-29b, eca-miR-93, eca-miR-98, and eca-miR-221 were significantly increased after the stimulations, which, as known anti-inflammatory miRNAs, could be candidates for therapeutic use in the treatment of OA.

These results lay the foundation for further research into the significance and efficacy of these miRNAs so that this knowledge can be improved in further experiments and, ideally, translated into therapeutic use.

Susceptibility to cartilage degeneration increases in an age-dependent manner and older cartilage exhibits increased catabolic factor expression leading to osteoarthritis (OA). While inhibition of cellular senescence can prevent age-related diseases, the understanding of the regulators governing cartilage senescence and the potential for senolytic intervention remains limited. Here, in vitro and in vivo results are reported, demonstrating for the first time that the transcriptional regulator, ZMIZ1, is upregulated in aged and OA cartilage, and that it acts through GATA4 to accelerate chondrocyte senescence and trigger cartilage deterioration. Furthermore, it is shown that K-7174 interferes with the ZMIZ1-GATA4 interaction and effectively hampers cartilage senescence and OA. It is proposed that inhibition of the ZMIZ1-GATA4 axis could be a valuable strategy for eliminating senescent chondrocytes and impeding OA development and that the relevant inhibitor, K-7174, could potentially be developed as a senolytic drug for managing cartilage senescence and age-related degeneration.

The use of miRNA in therapeutics has, since its discovery in 1993, attracted tremendous attention, and research in this area has progressed rapidly. Since the advent of RNA interference (RNAi), much about the nucleic acid siRNA has been elucidated. At the same time, no miRNA-based drugs have passed phase II clinical trials. A significant obstacle to miRNA-based drug development is the ease of degradation and relatively short half-life in vivo of miRNA. Hydrogels are networks of cross-linked polymer chains with the ability to 'swell'. They have shown remarkable capabilities that improve the properties of other researched carriers. In combination with miRNA modification strategies and inorganic carriers, hydrogel systems show promise for sustained miRNA delivery and the development of novel miRNA-based drugs. Although hydrogel systems have been reported recently, the focus has been predominantly on their wound-healing properties, with a dearth of information on their nucleic acid carrier abilities. This paper focuses more on the latest advancements in developing hydrogels as a carrier system, emphasizing the delivery of miRNA. This review will cover the methods of hydrogel fabrication, efforts for sustained miRNA release, biomedical applications, and future prospects.

The pathogenesis of cartilage injury and degeneration is exceptionally complex. In addition to being associated with osteoarthritis and trauma, factors such as age, gender, obesity, inflammation, and apoptosis of chondrocytes are also considered significant influencing factors. Due to the lack of direct blood supply, lymphatic circulation, and neural innervation, coupled with low metabolic activity, the self-repair capability of cartilage after injury is extremely limited, making its treatment quite challenging. Recent research indicated that ncRNA, a class of RNA transcribed from the genome that does not encode proteins, played a crucial regulatory role in various disease processes. Particularly noteworthy is its positive regulatory role in cartilage regeneration, achieved through the modulation of the inflammatory microenvironment, promotion of chondrocyte proliferation, inhibition of chondrocyte degradation, and facilitation of the recruitment and differentiation of bone marrow mesenchymal stem cells into chondrocytes. In the earlier phase, we conducted a review and outlook on therapeutic strategies for the regeneration of articular cartilage injuries. This article specifically focuses on summarizing the regulatory roles and research advancements of ncRNA in cartilage regeneration, as well as its contributions to the clinical application of gene therapy for cartilage defects.

Intra-articular drug injections are effective for osteoarthritis (OA), but challenges such as the complex microenvironment and rapid drug diffusion require frequent injections. Herein, we propose a biofunctional hydrogel-based strategy for prolonged drug delivery and microenvironment remodeling. We propose a strategy to functionalize zeolitic imidazolate framework-8 with tannic acid (TA-ZIF), anchor PTH-related peptide-1 (PTHrP-1) within this framework (TA-ZIF@P1) and incorporate a phenylboronic acid-modified gelatin-based hydrogel (GP hydrogel) drug delivery system (GP@TA-ZIF@P1, GPTP hydrogel) with responsive release properties that respond to the pathological microenvironments of OA. The GPTP hydrogel facilitated controlled, sustained release of PTHrP-1 via dynamic boronic esters, with in vitro and in vivo studies showing continuous release for over 28 days. It not only promotes chondrocyte proliferation but also exhibits significant cytoprotective effects under hyperactive ROS and IL-1β-induced conditions. Notably, transcriptome sequencing confirms that the GPTP hydrogel facilitates both chondrocyte proliferation and chondrogenesis under inflammatory conditions by deactivating Wnt/β-Catenin signaling pathways and enhancing the PI3K/AKT signaling pathway. Additionally, the GPTP hydrogel delays the catabolic metabolism of cartilage explants from mice in inflammatory environments. In a surgical model of mouse OA, we show that the intra-articular injection of GPTP hydrogels reduced periarticular bone remodeling and promoted the production of glycosaminoglycans while offering chondroprotection against cartilage degeneration. To sum up, this pioneering research on PTHrP-1 as a treatment for OA, combined with the GPTP hydrogel system, offers valuable insights and a paradigm for the controlled and sustained release of PTHrP-1, representing a significant advancement in OA treatment strategies.

Osteoarthritis (OA), a widespread degenerative joint disease, predominantly affects individuals from middle age onwards, exhibiting non-inflammatory characteristics. OA leads to the gradual deterioration of articular cartilage and subchondral bone, causing pain and reduced mobility. The risk of OA increases with age, making it a critical health concern for seniors. Despite significant research efforts and various therapeutic approaches, the precise causes of OA remain unclear.

This paper provides a thorough examination of OA characteristics, pathogenic mechanisms at various levels, and personalized treatment strategies for different OA stages. The review aims to enhance understanding of disease mechanisms and establish a theoretical framework for developing more effective therapeutic interventions.

This review systematically examines OA through multiple perspectives, integrating current knowledge of clinical presentation, pathological mechanisms, and associated signaling pathways. It assesses diagnostic methods and reviews both pharmacological and surgical treatments for OA, as well as emerging tissue engineering approaches to manage the disease. While therapeutic strategies such as exercise, anti-inflammatory drugs, and surgical interventions are employed to manage symptoms and modify joint structure, none have been able to effectively halt OA's advancement or achieve long-lasting symptom relief. Tissue engineering strategies, such as cell-seeded scaffolds, supportive matrices, and growth factor delivery, have emerged as promising approaches for cartilage repair and OA treatment. To combat the debilitating effects of OA, it is crucial to investigate the molecular basis of its pathogenesis and seek out innovative therapeutic targets for more potent preventive and treatment strategies.

Abnormalities in glycolytic pathways are prominent factors in the pathogenesis of osteoarthritis (OA). The key glycolytic enzyme Hexokinase 2 (HK2) is highly expressed in chondrocytes in OA; however, its role remains unclear. Pulsed electromagnetic field (PEMF) is commonly used for the treatment of OA. However, the role of PEMF in cartilage damage and the underlying mechanisms are not well understood. Herein, we found that HK2 suppression down-regulated catabolic pathways and alleviated inflammatory responses in OA chondrocytes, whereas HK2 overexpression stimulated inflammation and catabolic levels; moreover, inhibition of HK2 has potential anti-inflammatory and anti-catabolic properties by regulating the expression of HMGA2. PEMF dramatically inhibited the increase in glycolytic activity and catabolic metabolism level in OA and could alleviate the OA phenotype by modulating the HK2/HMGA2 signaling axis. Suppressing HK2 via adeno-associated virus (AAV) in articular cartilage demonstrated that PEMF reduces cartilage damage and OA symptoms through HK2 knockdown. Furthermore, the HK2 inhibitor Lonidamine, in combination with PEMF, more effectively ameliorated cartilage degeneration in OA. Overall, our findings improve understanding of HK2's role in OA and offer new insights for targeting HK2 in treatment. Furthermore, our results provide new clues for the reducing of catabolism and cartilage damage using PEMF.

Arthritis is a chronic inflammatory disease that causes joint damage, with osteoarthritis (OA) and rheumatoid arthritis (RA) being the most common types. Both conditions are characterized by cartilage degradation due to an imbalance between repair and breakdown processes. Chondrocytes, the key cells in articular cartilage, maintain its structure by producing an extracellular matrix rich in aggrecan and type II collagen (COL2). MicroRNAs (miRNAs), small noncoding RNAs, regulate genes critical for cartilage balance and are involved in the progression and treatment of OA and RA. Recently, herbal medicines have gained attention for arthritis treatment. Ugonin P, a flavonoid from Helminthostachys zeylanica Hook, is known for its antioxidant and anticancer effects, but its role in cartilage homeostasis is unclear. This study explores ugonin P's chondrogenic effects and its molecular mechanisms involving miRNA regulation. Analysis of Gene Expression Omnibus (GEO) data and clinical samples revealed reduced aggrecan and COL2 levels in OA and RA, while miR-3074-5p levels were elevated, suppressing these proteins. Ugonin P, without affecting cell viability, enhanced aggrecan and COL2 production and promoted chondrocyte differentiation by downregulating miR-3074-5p and activating MAPK pathways. These findings suggest ugonin P as a promising therapeutic candidate for arthritis management.

Osteoarthritis is a progressive, irreversible debilitating whole joint disease that affects millions of people worldwide. Despite the availability of various options (non-pharmacological and pharmacological treatments and therapy, orthobiologics, and surgical interventions), none of them can definitively cure osteoarthritis in patients. Strategies based on the controlled release of therapeutic compounds via biocompatible materials may provide powerful tools to enhance the spatiotemporal delivery, expression, and activities of the candidate agents as a means to durably manage the pathological progression of osteoarthritis in the affected joints upon convenient intra-articular (injectable) delivery while reducing their clearance, dissemination, or side effects. The goal of this review is to describe the current knowledge and advancements of controlled release to treat osteoarthritis, from basic principles to applications in vivo using therapeutic recombinant molecules and drugs and more innovatively gene sequences, providing a degree of confidence to manage the disease in patients in a close future.

Osteoarthritis (OA) is a degenerative whole-joint disease in which the synovium and joint cartilage become inflamed and damaged. The essential role of inflammation in the development of OA has been recognized recently. Accordingly, simultaneous regulation of local inflammation and tissue degeneration is proposed as a promising therapeutic strategy. Herein, multifunctional biomimetic apoptotic nanovesicles (Apo-NVs) are constructed with plasma membrane derived from apoptotic T cells. The anti-inflammatory microRNA-124 is further encapsulated into Apo-NVs in the hope of achieving an enhanced immunomodulatory effect. It is found that apoptotic nanovesicles, including Apo-NVs and Apo-NVs-miR-124, both efficiently promote the M2 repolarization of M1 macrophages and inhibit the degenerative phenotype of chondrocytes. Further in vivo studies show that Apo-NVs and Apo-NVs-miR-124 alleviate synovial inflammation and protect cartilage tissue from degeneration in OA mice. The study highlights the potential of Apo-NVs in treating OA and other inflammation-related diseases.

Osteoarthritis (OA) is the most common disease in aging joints and has characteristics of cartilage destruction and inflammation. It is currently considered a metabolic disease, and the CH25H-CYP7B1-RORα axis of cholesterol metabolism in chondrocytes plays a crucial catabolic regulatory role in its pathogenesis. Targeting of this axis in chondrocytes may provide a therapeutic approach for OA treatment. Here, in this study, we propose to use a combination of stem cell-recruiting hydrogels and lipid nanoparticles (LNPs) that modulate cholesterol metabolism to jointly promote a regenerative microenvironment. Specifically, we first developed an injectable, bioactive hydrogel composed of self-assembling peptide nanofibers that recruits endogenous synovial stem cells (SMSCs) and promotes their chondrogenic differentiation. At the same time, LNPs that regulate cholesterol metabolism are incorporated into the hydrogel and slowly released, thereby improving the inflammatory environment of OA. Enhancements were noted in the inflammatory conditions associated with OA, alongside the successful attraction of mesenchymal stem cells (MSCs) from the synovial membrane. These cells were then observed to differentiate into chondrocytes, contributing to effective cartilage restoration and chondrocyte regeneration, thereby offering a promising approach for OA treatment. In summary, this approach provides a feasible siRNA-based therapeutic option, offering a potential nonsurgical solution for treatment of OA.

Osteoarthritis (OA) poses a significant challenge in orthopedics. Inflammatory pathways are regarded as central mechanisms in the onset and progression of OA. Growing evidence suggests that senescence acts as a mediator in inflammation-induced OA. Given the lack of effective treatments for OA, there is an urgent need for a clearer understanding of its pathogenesis. In this review, we systematically summarize the cross-talk between cellular senescence and inflammation in OA. We begin by focusing on the mechanisms and hallmarks of cellular senescence, summarizing evidence that supports the relationship between cellular senescence and inflammation. We then discuss the mechanisms of interaction between cellular senescence and inflammation, including senescence-associated secretory phenotypes (SASP) and the effects of pro- and anti-inflammatory interventions on cellular senescence. Additionally, we focus on various types of cellular senescence in OA, including senescence in cartilage, subchondral bone, synovium, infrapatellar fat pad, stem cells, and immune cells, elucidating their mechanisms and impacts on OA. Finally, we highlight the potential of therapies targeting senescent cells in OA as a strategy for promoting cartilage regeneration.

Untreated articular cartilage injuries often result in severe chronic pain and dyskinesia. Current repair strategies have limitations in effectively promoting articular cartilage repair, underscoring the need for innovative therapeutic approaches. A gene-activated matrix (GAM) is a promising and comprehensive therapeutic strategy that integrates tissue-engineered scaffold-guided gene therapy to promote long-term articular cartilage repair by enhancing gene retention, reducing gene loss, and regulating gene release. However, for effective articular cartilage repair, the GAM scaffold must mimic the complex gradient structure of natural articular cartilage. Three-dimensional (3D) bioprinting technology has emerged as a compelling solution, offering the ability to precisely create complex microstructures that mimic the natural articular cartilage. In this review, we summarize the recent research progress on GAM and 3D bioprinted scaffolds in articular cartilage tissue engineering (CTE), while also exploring future challenges and development directions. This review aims to provide new ideas and concepts for the development of gene-activated bioprinted scaffolds with specific properties tailored to meet the stringent requirements of articular cartilage repair.

Osteoarthritis (OA) is characterized by symptoms such as abnormal lubrication function of synovial fluid and heightened friction on the cartilage surface in its early stages, prior to evident cartilage damage. Current early intervention strategies employing lubricated hydrogels to shield cartilage from friction often overlook the significance of hydrogel-cartilage adhesion and enhancement of the cartilage extracellular matrix (ECM). Herein, we constructed a hydrogel based on dihydrazide-modified hyaluronic acid (HA) (AHA) and catechol-conjugated aldehyde-modified HA (CHA), which not only adheres to the cartilage surface as an effective lubricant but also improves the extracellular environment of chondrocytes in OA. Material characterization experiments on AHA/CHA hydrogels with varying concentrations validated their exceptional self-healing capabilities, superior injectability and viscoelasticity, sustained adhesion strength to cartilage, and a low friction coefficient. Chondrocytes exhibited robust adhesion and proliferation on the AHA/CHA hydrogel surface, with the upregulation of cartilage matrix protein expression. Intra-articular injection of AHA/CHA hydrogels was performed following destabilization of the medial meniscus (DMM) surgery in mice to assess its protective effect on cartilage. The AHA/CHA hydrogel effectively attenuated the degree of cartilage wear, facilitated chondrocytes' anabolic metabolism, and restored the ECM of cartilage. Therefore, the AHA/CHA hydrogel emerges as a promising therapeutic approach in clinical practices of OA treatment.

Bioactive molecules have shown great promise for effectively regulating various bone formation processes, rendering them attractive therapeutics for bone regeneration. However, the widespread application of bioactive molecules is limited by their low accumulation and short half-lives in vivo. Hydrogels have emerged as ideal carriers to address these challenges, offering the potential to prolong retention times at lesion sites, extend half-lives in vivo and mitigate side effects, avoid burst release, and promote adsorption under physiological conditions. This review systematically summarizes the recent advances in the development of bioactive molecule-loaded hydrogels for bone regeneration, encompassing applications in cranial defect repair, femoral defect repair, periodontal bone regeneration, and bone regeneration with underlying diseases. Additionally, this review discusses the current strategies aimed at improving the release profiles of bioactive molecules through stimuli-responsive delivery, carrier-assisted delivery, and sequential delivery. Finally, this review elucidates the existing challenges and future directions of hydrogel encapsulated bioactive molecules in the field of bone regeneration.

OA is a chronic disease characterized by cartilage degeneration and inflammation, with no approved disease-modifying drugs. This study aimed to identify pathogenic genes and elucidate their mechanism in OA.

We systematically identified pathogenic genes combined sing-cell and bulk transcriptome profiles of cartilage tissues in OA. Adenovirus carrying the serpin peptidase inhibitor clade E member 2 (serpinE2) or exogenous serpinE2 was injected into monosodium iodoacetate (MIA)-induced OA-model rats. Histological analysis, immunohistochemistry and Alcian blue staining were performed. In vitro, immunofluorescence, quantitative real-time PCR (RT-qPCR), ELISA and western blot assays were performed.

serpinE2 exhibited elevated expression and hypomethylation, showing a positive association with collagen pathway activities in patients with OA. Silencing serpinE2 aggravated MIA-induced knee cartilage degeneration in OA-model rats. Conversely, the intra-articular injection of exogenous serpinE2 ameliorated articular cartilage degeneration, reduced pain-related behavioural responses and relieve synovitis in MIA-induced OA-model rats. Exogenous serpinE2 not only attenuated the elevation of NLRP3, IL-1β and caspase1 expression levels but also restored the reduction in cell viability induced by lipopolysaccharide (LPS) in chondrocytes. Mechanistically, we found that exogenous serpinE2 inhibited LPS-induced reactive oxygen species (ROS) release and NF-κB signalling activation.

serpinE2 plays a protective role in cartilage and synovium tissues, suggesting that serpinE2 gene transfer or molecules that upregulate serpinE2 expression could be therapeutic candidates for OA.

Osteoporotic bone defects refer to the disruption of bone structural integrity in patients with osteoporosis and pose a substantial challenge to orthopedic surgeons. In this study, we developed a biomimetic hydrogel to improve the osteogenic microenvironment and promote stem cell homing. This hydrogel served as a container for S-nitrosoglutathione and Ca2+, promoting the release of bioactive nitric oxide (NO) from bone marrow mesenchymal stem cells (BMSCs) and human vascular endothelial cells and activating the NO/cyclic guanosine monophosphate signaling pathway. These changes promote osteogenic and angiogenic couplings. The hydrogel simultaneously recruited BMSCs by conjugating the stem cell homing peptide SKPPGTSS. Using a rat distal femoral defect model, it was demonstrated that this hydrogel can effectively increase the formation of bone tissue and new blood vessels and has immune-regulating functions. We envision that this hydrogel may be a minimally invasive yet highly effective strategy for expediting the healing of osteoporotic bone defects.

The progression of osteoarthritis (OA) is dramatically accelerated by excessive reactive oxygen species (ROS)-induced apoptosis of chondrocytes and the inflammatory response of synovial macrophages. In this study, we developed an injectable hydrogel with a catalase-mimicking nanozyme activity as a therapeutic agent for OA. In vitro experiments confirmed that the HA and peroxide-mimetic nanoenzyme-enhanced hydrogel, containing ε-polylysine/Mn1.8Co1.2O4 (ε-PLE/MnCoO) nanoparticles, continuously eliminated ROS and inflammatory cytokines while promoting the polarization of inflammatory macrophages (M1 phenotype) towards anti-inflammatory macrophages (M2 phenotype) in dysfunctional microenvironments. When used for intraarticular injections in OA models, the nanoenzyme-enhanced hydrogel effectively reduced oxidative stress by scavenging ROS and regulating the immune microenvironment. It resulted in a subsequent reduction in the expression of inflammatory factors, including MMP-13, TNF-α, IL-1β, and iNOS in both the synovium and joint fluid. Moreover, cartilage repair was enhanced by the promotion of COL-2 and SOX-9 expression in the cartilage tissue, whereas osteophyte formation in OA was reduced. This study introduced an innovative treatment strategy for the clinical management of OA, demonstrating its significant potential for application in treating OA.

Cartilage regeneration relies on adequate and continuous bioenergy supply to facilitate cellular differentiation and extracellular matrix synthesis. Chondrocytes frequently undergo energy stress under pathological conditions, characterized by disrupted cellular metabolism and reduced adenosine triphosphate (ATP) levels. However, there has limited progress in modulating energy metabolism for cartilage regeneration thus far. Here, we developed bioenergetic-active exosomes (Suc-EXO) to promote cartilage regeneration and homeostasis maintenance. Suc-EXO exhibited a 5.42-fold increase in ATP content, enabling the manipulation of cellular energy metabolism by fueling the TCA cycle. With continuous energy supply, Suc-EXO promoted BMSC chondrogenic differentiation via the P2X7-mediated PI3K-AKT pathway. Moreover, Suc-EXO improved chondrocyte anabolism and mitochondrial homeostasis via the P2X7-mediated SIRT3 pathway. In a rabbit cartilage defect model, the Suc-EXO-encapsulated hydrogel notably promoted cartilage regeneration and maintained neocartilage homeostasis, leading to 2.26 and 1.53 times increase in Col2 and ACAN abundance, respectively. These findings make a remarkable breakthrough in modulating energy metabolism for cartilage regeneration, offering immense potential for clinical translation.

This review summarizes the latest progress in orthopedic nanotechnology, explores innovative applications of nanofibers in tendon repair, and evaluates the potential of selenium and cerium oxide nanoparticles in osteoarthritis and osteoblast differentiation. This review also describes the emerging applications of injectable hydrogels in cartilage engineering, emphasizing the critical role of interdisciplinary research and highlighting the challenges and future prospects of integrating nanotechnology into orthopedic clinical practice. This comprehensive approach provides a holistic perspective on the transformative impact of nanotechnology in orthopedics, offering valuable insights for future research and clinical applications.

Altering the mechanisms of tumor cell death and overcoming the limitations of traditional chemotherapy is pivotal to contemporary tumor treatment. Inducing ferroptosis, while circumventing safety concerns associated with ferrous vectors, through nonferrous ferroptosis is a promising but underexplored frontier in cancer therapy. Histidine phosphatase (LHPP) has emerged as a novel therapeutic target in treating hepatocellular carcinoma (HCC), but the precise mechanism of LHPP against HCC remains unclear. Herein, we explore the effects of upregulating LHPP expression on ferroptosis and tumor immunogenicity induction by simply delivering a miRNA-363-5p inhibitor (miR-363-5pi) via a previously optimized gemcitabine-oleic acid (GOA) prodrug. Efficient miRNA encapsulation was achieved through hydrogen bonding at an optimized GOA/miRNA molar feed ratio of 250:1, affording spherical nanoparticles with a uniform hydrodynamic size of 147.1 nm and a negative potential of -21.5 mV. The mechanism of this LHPP-ferroptosis crosstalk is disclosed to be an inhibited phosphorylation of the PI3K/Akt pathway, leading to a remarkable tumor inhibition rate of 88.2% in nude mice bearing Bel-7402 tumor xenografts via a combination of LHPP-triggered nonferrous ferroptosis and GOA-induced chemotherapy. The biocompatibility of GOA/miR-363-5pi is strongly supported by their non-hematologic toxicity and insignificant organ damage. In addition, the tumor immunogenic activation potential of GOA/miR-363-5pi was finally explored. Overall, this study is the first work that elucidates the precise mechanism of LHPP for treating HCC via ferroptosis induction and achieves the transformation of chemotherapy and gene therapy into ferroptosis activation with tumor cell immunogenicity, which lays a new therapeutic foundation for the clinical treatment of HCC.

Cartilage defect is one of the common tissue defect clinical diseases and may finally lead to osteoarthritis (OA) which threat patients' physical and psychological health. Polysaccharide is the main component of extracellular matrix (ECM) in cartilage tissue. In the past decades, polysaccharide-based hydrogels have shown great potential for cartilage regeneration considering unique qualities such as biocompatibility, enhanced cell proliferation, drug delivery, low toxicity, and many others. Structures such as chain length and chain branching make polysaccharides have different physical and chemical properties. In this review, cartilage diseases and current treatment options of polysaccharide-based hydrogels for cartilage defection repair were illustrated. We focus on how components and structures of recently developed materials affect the performance. The challenges and perspectives for polysaccharide-based hydrogels in cartilage repair and regeneration were also discussed in depth.

Despite critical advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy based on the delivery of therapeutic genetic sequences has strong value to offer effective, durable options to decisively manage such disorders. Furthermore, scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy, allowing for the spatiotemporal delivery of candidate genes to sites of injury. Among the many scaffolds for musculoskeletal research, hydrogels raised increasing attention in addition to other potent systems (solid, hybrid scaffolds) due to their versatility and competence as drug and cell carriers in tissue engineering and wound dressing. Attractive functionalities of hydrogels for musculoskeletal therapy include their injectability, stimuli-responsiveness, self-healing, and nanocomposition that may further allow to upgrade of them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. Such functionalized hydrogels may also be tuned to successfully transfer therapeutic genes in a minimally invasive manner in order to protect their cargos and allow for their long-term effects. In light of such features, this review focuses on functionalized hydrogels and demonstrates their competence for the treatment of musculoskeletal disorders using gene therapy procedures, from gene therapy principles to hydrogel functionalization methods and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are being discussed in the perspective of translation in patients. STATEMENT OF SIGNIFICANCE: Despite advances in regenerative medicine, the generation of definitive, reliable treatments for musculoskeletal diseases remains challenging. Gene therapy has strong value in offering effective, durable options to decisively manage such disorders. Scaffold-mediated gene therapy provides powerful alternatives to overcome hurdles associated with classical gene therapy. Among many scaffolds for musculoskeletal research, hydrogels raised increasing attention. Functionalities including injectability, stimuli-responsiveness, and self-healing, tune them as "intelligently" efficient and mechanically strong platforms, rather than as just inert vehicles. This review introduces functionalized hydrogels for musculoskeletal disorder treatment using gene therapy procedures, from gene therapy principles to functionalized hydrogels and applications of hydrogel-mediated gene therapy for musculoskeletal disorders, while remaining challenges are discussed from the perspective of translation in patients.

Increasing attention has been paid to the development of effective strategies for articular cartilage (AC) and osteochondral (OC) regeneration due to their limited self-reparative capacities and the shortage of timely and appropriate clinical treatments. Traditional cell-dependent tissue engineering faces various challenges such as restricted cell sources, phenotypic alterations, and immune rejection. In contrast, endogenous tissue engineering represents a promising alternative, leveraging acellular biomaterials to guide endogenous cells to the injury site and stimulate their intrinsic regenerative potential. This review provides a comprehensive overview of recent advancements in endogenous tissue engineering strategies for AC and OC regeneration, with a focus on the tissue engineering triad comprising endogenous stem/progenitor cells (ESPCs), scaffolds, and biomolecules. Multiple types of ESPCs present within the AC and OC microenvironment, including bone marrow-derived mesenchymal stem cells (BMSCs), adipose-derived mesenchymal stem cells (AD-MSCs), synovial membrane-derived mesenchymal stem cells (SM-MSCs), and AC-derived stem/progenitor cells (CSPCs), exhibit the ability to migrate toward injury sites and demonstrate pro-regenerative properties. The fabrication and characteristics of scaffolds in various formats including hydrogels, porous sponges, electrospun fibers, particles, films, multilayer scaffolds, bioceramics, and bioglass, highlighting their suitability for AC and OC repair, are systemically summarized. Furthermore, the review emphasizes the pivotal role of biomolecules in facilitating ESPCs migration, adhesion, chondrogenesis, osteogenesis, as well as regulating inflammation, aging, and hypertrophy-critical processes for endogenous AC and OC regeneration. Insights into the applications of endogenous tissue engineering strategies for in vivo AC and OC regeneration are provided along with a discussion on future perspectives to enhance regenerative outcomes.

During the development of temporomandibular joint osteoarthritis, endochondral ossification is compromised which leads to condylar degeneration; miR-335-5p in endochondral ossification in osteoarthritic condylar cartilage tissue remains unclear.

Up-regulated microRNA and its target gene were searched for endochondral ossification in osteoarthritis articular cartilage. The effect of increased or decreased miR-335-5p on endochondral ossification was evaluated by transfecting miR-335-5p mimics or miR-335-5p inhibitor in vitro in chondrocytes C28/I2. Finally, we injected the temporomandibular joint of rats intra-articularly with agomiR-335 in a unilateral anterior crossbite rat model to determine the in vivo regulation of miR-335.

After the onset of temporomandibular joint osteoarthritis, miR-335-5p levels were gradually up-regulated, whereas endochondral ossification-related genes were down-regulated in condylar cartilage specimens. Our results showed that miR-335 inhibited endochondral ossification after administration of a miR-335 antagonist into the temporomandibular joint articular cavity of a unilateral anterior crossbite rat model. AgomiR-335, a miR-335 agonist, inhibited matrix mineralization in fibrocartilage stem cells in vitro and then miR-335-5p negatively regulated chondrocyte activity by directly targeting SP1 via promoting transforming growth factor-β/Smad signalling.

miR-335-5p can significantly inhibit endochondral ossification; therefore, its inhibition may be beneficial for the treatment of temporomandibular joint osteoarthritis.