Intervertebral disc degeneration (IVDD) is a leading cause of low back pain (LBP), contributing significantly to global disability and productivity loss. Its pathogenesis involves complex processes, including inflammation, cellular senescence, angiogenesis, fibrosis, neural ingrowth, and sensitization. Emerging evidence highlights macrophages as central immune regulators infiltrating degenerated discs, with macrophage polarization implicated in IVDD progression. However, the mechanisms linking macrophage polarization to IVDD pathology remain poorly elucidated.

A comprehensive literature review was conducted by searching major databases (PubMed, Web of Science, and Scopus) for studies published in the last decade (2014-2024). Keywords included "intervertebral disc degeneration," "macrophage polarization," "inflammation," "senescence," and "therapeutic strategies." Relevant articles were selected, analyzed, and synthesized to evaluate the role of macrophage polarization in IVDD.

Macrophage polarization dynamically influences IVDD through multiple pathways. Pro-inflammatory M1 macrophages exacerbate disc degeneration by amplifying inflammatory cytokines (e.g., TNF-α, IL-1β), promoting cellular senescence, and stimulating abnormal angiogenesis and neural ingrowth. In contrast, anti-inflammatory M2 macrophages may mitigate degeneration by suppressing inflammation and enhancing tissue repair. Therapeutic strategies targeting macrophage polarization include pharmacological agents (e.g., cytokines, small-molecule inhibitors), biologic therapies, gene editing, and physical interventions. Challenges persist, such as incomplete understanding of polarization triggers, lack of targeted delivery systems, and limited translational success in preclinical models.

Macrophage polarization is a pivotal regulator of IVDD pathology, offering promising therapeutic targets. Future research should focus on elucidating polarization mechanisms, optimizing spatiotemporal control of macrophage phenotypes, and developing personalized therapies. Addressing these challenges may advance innovative strategies to halt or reverse IVDD progression, ultimately improving clinical outcomes for LBP patients.

Exosomes derived from bone marrow mesenchymal stem cells (BMSCs) and heme oxygenase 1 (HO‑1) attenuate intervertebral disc degeneration (IVDD). However, whether BMSC‑derived exosomes attenuate IVDD by delivering HO‑1 to nucleus pulposus (NP) cells remains to be elucidated. Mouse BMSCs were characterized by multilineage differentiation and surface marker molecule detection. Exosomes Exo and Exo‑HO‑1 were isolated from BMSCs and HO‑1‑overexpressing BMSCs by ultracentrifugation and characterized by observing their morphology, detecting the exosome marker proteins, tumor susceptibility gene 101 (TSG101) and CD63 and analyzing their particle size. Interleukin‑1 β (IL‑1β)‑stimulated NP cells were used as the IVDD cell model. The influence of Exo or Exo‑HO‑1 on IL‑1β‑urged apoptosis and senescence in NP cells was determined by flow cytometry, western blotting and senescence‑associated β‑galactosidase (SA‑β‑gal) staining. Exo and Exo‑HO‑1 did not vary in size or morphology. Exo‑HO‑1 markedly repressed IL‑1β‑prompted apoptosis in NP cells, accompanied with a prominent increase in Cleaved caspase 3 and Bax protein levels and a marked decrease in Bcl‑2 protein levels. Exo and Exo‑HO‑1 both decreased the number of SA‑β‑gal‑positive NP cells and arrested NP cells in the G1 phase. Exo‑HO‑1 had stronger effects than Exo, suggesting that Exo‑HO‑1 can weaken IL‑1β‑induced NP cell senescence. In addition, Exo and Exo‑HO‑1 repressed IL‑1β mediating the phosphorylation of p65 and nuclear translocation of p65. In conclusion, HO‑1‑overexpressing BMSC‑derived exosomes blocked the nuclear factor‑kappa B signaling in IL‑1β‑stimulated NP cells, thus impairing cell apoptosis and senescence.

Intervertebral disc degeneration is a multifactorial degenerative disease that poses a significant threat to the health of the elderly population. Current treatments primarily focus on physical therapy, medication, and surgery to alleviate symptoms associated with disc compression but do not address the progression of degeneration. Therefore, this review aimed to explore the potential of extracellular vesicle therapy as a novel preventive strategy to delay degeneration and enhance tissue repair in intervertebral discs. We cover the pathogenic mechanisms underlying intervertebral disc degeneration, including inflammation, apoptosis, pyroptosis, ferroptosis, autophagy dysregulation, and the roles of non-coding RNAs. Subsequently, we discussed the therapeutic potential of extracellular vesicles and their molecular components, such as proteins, RNAs, and lipids, in modulating these pathways to counter intervertebral disc degeneration. We provides a comprehensive review of the significant role of extracellular vesicle cargo in mediating repair mechanisms. It discusses the functional enhancement advantages exhibited by extracellular vesicles under current bioengineering modifications and drug loading. The challenges and future prospects of utilizing extracellular vesicle therapy to treat this degenerative condition are also summarized.

Intervertebral disc degeneration is a degenerative disease where inflammation and immune responses play significant roles. Macrophages, as key immune cells, critically regulate inflammation through polarization into different phenotypes. In recent years, the role of macrophages in inflammation-related degenerative diseases, such as intervertebral disc degeneration, has been increasingly recognized. Macrophages construct the inflammatory microenvironment of the intervertebral disc and are involved in regulating intervertebral disc cell activities, extracellular matrix metabolism, intervertebral disc vascularization, and innervation, profoundly influencing the progression of disc degeneration. To gain a deeper understanding of the inflammatory microenvironment of intervertebral disc degeneration, this review will summarize the role of macrophages in the pathological process of intervertebral disc degeneration, analyze the regulatory mechanisms involving macrophages, and review therapeutic strategies targeting macrophage modulation for the treatment of intervertebral disc degeneration. These insights will be valuable for the treatment and research directions of intervertebral disc degeneration.

Intervertebral disc degeneration is the leading cause of low back pain, imposing significant burdens on patients, societies, and economies. Advancements in regenerative medicine have spotlighted extracellular vesicles as promising nanoparticles for intervertebral disc degeneration treatment. Extracellular vesicles retain the potential of cell therapy and serve as carriers to deliver their cargo to target cells, thereby regulating cell activity. This review summarizes the biogenesis and molecular composition of extracellular vesicles and explores their therapeutic roles in intervertebral disc degeneration treatment through various mechanisms. These mechanisms include mitigating cell loss and senescence, delaying extracellular matrix degeneration, and modulating the inflammatory microenvironment. Additionally, it highlights recent efforts in engineering extracellular vesicles to enhance their targeting and therapeutic efficacy. The integration of extracellular vesicle-based acellular therapy is anticipated to drive significant advancements in disc regenerative medicine.

Existing clinical treatment strategies often fail to effectively address the challenges associated with regenerating degenerated intervertebral discs. As a new regenerative medicine strategy, the extracellular vesicle strategy avoids the risks associated with cell transplantation and shows great promise in treating intervertebral disc degeneration by carrying therapeutic cargo. This review comprehensively examines the latest research, underlying mechanisms, and therapeutic potential of extracellular vesicles, offering a promising new strategy for intervertebral disc degeneration treatment.

Bone marrow mesenchymal stem cell (BMSC)-derived exosomes possess therapeutic potential against degenerative diseases. This study aimed to investigate the effects of BMSC-derived exosomes on intervertebral disc degeneration (IVDD) and explore the underlying molecular mechanisms. Through transcriptome sequencing and histological analysis, we observed a significant increase in HIF-1α expression in degenerative nucleus pulposus (NP) tissues. The addition of HIF-1α resulted in elevated expression of inflammatory factors IL-1β and IL-6, higher levels of matrix-degrading enzyme MMP13, and lower expression of aggrecan in NP cells. Co-culturing with BMSCs diminished the expression of HIF-1α, MMP13, IL-1β, and IL-6 in degenerative NP cells induced by overload pressure. miRNA chip analysis and PCR validation revealed that miR-145a-5p was the primary miRNA carried by BMSC-derived exosomes. Overexpression of miR-145a-5p was effective in minimizing the expression of HIF-1α, MMP13, IL-1β, and IL-6 in degenerative NP cells. Luciferase reporter assays confirmed USP31 as the target gene of miR-145a-5p, and the regulation of NP cells by BMSC-derived exosomes via miR-145a-5p was dependent on USP31. In conclusion, BMSC-derived exosomes alleviated IVDD through the miR-145a-5p/USP31/HIF-1α signaling pathway, providing valuable insights into the treatment of IVDD.

Skeletal diseases impose a considerable burden on society. The clinical and tissue-engineering therapies applied to alleviate such diseases frequently result in complications and are inadequately effective. Research has shifted from conventional therapies based on mesenchymal stem cells (MSCs) to exosomes derived from MSCs. Exosomes are natural nanocarriers of endogenous DNA, RNA, proteins, and lipids and have a low immune clearance rate and good barrier penetration and allow targeted delivery of therapeutics. MSC-derived exosomes (MSC-exosomes) have the characteristics of both MSCs and exosomes, and so they can have both immunosuppressive and tissue-regenerative effects. Despite advances in our knowledge of MSC-exosomes, their regulatory mechanisms and functionalities are unclear. Here we review the therapeutic potential of MSC-exosomes for skeletal diseases.

The escalating threat of bone-related diseases poses a significant challenge to human health. Mesenchymal stem cell (MSC)-derived extracellular vesicles (MSC-EVs), as inherent cell-secreted natural products, have emerged as promising treatments for bone-related diseases. Leveraging outstanding features such as high biocompatibility, low immunogenicity, superior biological barrier penetration, and extended circulating half-life, MSC-EVs serve as potent carriers for microRNAs (miRNAs), long no-code RNAs (lncRNAs), and other biomolecules. These cargo molecules play pivotal roles in orchestrating bone metabolism and vascularity through diverse mechanisms, thereby contributing to the amelioration of bone diseases. Additionally, engineering modifications enhance the bone-targeting ability of MSC-EVs, mitigating systemic side effects and bolstering their clinical translational potential. This review comprehensively explores the mechanisms through which MSC-EVs regulate bone-related disease progression. It delves into the therapeutic potential of MSC-EVs as adept drug carriers, augmented by engineered modification strategies tailored for osteoarthritis (OA), rheumatoid arthritis (RA), osteoporosis, and osteosarcoma. In conclusion, the exceptional promise exhibited by MSC-EVs positions them as an excellent solution with considerable translational applications in clinical orthopedics.

Intervertebral disc degeneration (IDD) is a disease that severely affects spinal health and is prevalent worldwide. Mesenchymal stem cells (MSCs) and their derived extracellular vesicles (EVs) have regenerative potential and have emerged as promising therapeutic tools for treating degenerative discs. However, challenges such as the harsh microenvironment of degenerated intervertebral discs and EVs' limited stability and efficacy have hindered their clinical application. In recent years, hydrogels have attracted much attention in the field of IDD therapy because they can mimic the physiologic microenvironment of the disc and provide a potential solution by providing a suitable growth environment for MSCs and EVs. This review introduced the biological properties of MSCs and their derived EVs, summarized the research on the application of MSCs and EVs in IDD, summarized the current clinical trial studies of MSCs and EVs, and also explored the mechanism of action of MSCs and EVs in intervertebral discs. In addition, plenty of research elaborated on the mechanism of action of different classified hydrogels in tissue engineering, the synergistic effect of MSCs and EVs in promoting intervertebral disc regeneration, and their wide application in treating IDD. Finally, the challenges and problems still faced by hydrogel-loaded MSCs and EVs in the treatment of IDD are summarized, and potential solutions are proposed. This paper outlines the synergistic effects of MSCs and EVs in treating IDD in combination with hydrogels and aims to provide theoretical references for future related studies.

As a global public health problem, low back pain (LBP) caused by intervertebral disc degeneration (IDD) seriously affects patients' quality of life. In addition, the prevalence of IDD tends to be younger, which brings a huge burden to individuals and society economically. Current treatments do not delay or reverse the progression of IDD. The emergence of biologic therapies has brought new hope for the treatment of IDD. Among them, extracellular vesicles (EVs), as nanoscale bioactive substances that mediate cellular communication, have now produced many surprising results in the research of the treatment of IDD. This article reviews the mechanisms and roles of EVs in delaying IDD and describes the prospects and challenges of EVs.

Intervertebral disc (ID) degeneration (IDD) is one of the main causes of chronic low back pain, and degenerative lesions are usually caused by an imbalance between catabolic and anabolic processes in the ID. The environment in which the ID is located is harsh, with almost no vascular distribution within the disc, and the nutrient supply relies mainly on the diffusion of oxygen and nutrients from the blood vessels located under the endplate. The stability of its internal environment also plays an important role in preventing IDD. The main feature of disc degeneration is a decrease in the number of cells. Mesenchymal stem cells have been used in the treatment of disc lesions due to their ability to differentiate into nucleus pulposus cells in a nonspecific anti-inflammatory manner. The main purpose is to promote their regeneration. The current aim of stem cell therapy is to replace the aged and metamorphosed cells in the ID and to increase the content of the extracellular matrix. The treatment of disc degeneration with stem cells has achieved good efficacy, and the current challenge is how to improve this efficacy. Here, we reviewed current treatments for disc degeneration and summarize studies on stem cell vesicles, enhancement of therapeutic effects when stem cells are mixed with related substances, and improvements in the efficacy of stem cell therapy by adjuvants under adverse conditions. We reviewed the new approaches and ideas for stem cell treatment of disc degeneration in order to contribute to the development of new therapeutic approaches to meet current challenges.

This study aimed to determine the effects of bone marrow mesenchymal stem cells (BMSCs)-derived exosomes (BMSC-EXO) on atherosclerosis (AS), and its related underlying mechanisms.

Exosomes were isolated from mouse BMSCs, and identified by transmission electron microscopy (TEM), Nanosight (NTA), and western blot. A mouse AS model was established, and exosomes were injected into the tail vein. Total cholesterol (TC) and triglycerides (TG) were detected using their corresponding assay kits. The contents of IL-1β and IL-18 in serum were detected by ELISA. The mRNA and protein expression levels of GSDMD, Caspase1, and NLRP3 were detected by qRT-PCR and Western blot. Finally, aortic tissues in the Model and BMSC-EXO groups were sent for sequencing.

TEM, NTA, and western blot indicated successful isolation of exosomes. Compared with the control group, the TC, TG contents, IL-1β and IL-18 concentrations of the mice in the Model group were significantly increased; nonetheless, were significantly lower after injected with BMSC-EXO than those in the Model group (p < 0.05). Compared with the control group, the expressions of NLRP3, caspase-1 and GSDMD were significantly up-regulated in the Model group (p < 0.05), while the expressions of NLRP3, caspase-1, and GSDMD were significantly down-regulated by BMSC-EXO. By sequencing, a total of 3852 DEGs were identified between the Model and BMSC-EXO group and were significantly enriched in various biological processes and pathways related to mitochondrial function, metabolism, inflammation, and immune response.

AS can induce pyroptosis, and BMSC-EXO can reduce inflammation and alleviate the progression of AS by inhibiting NLRP3/Caspase-1/GSDMD in the pyroptosis pathway.