Surface modification of extracellular vesicles with polyoxazolines to enhance their plasma stability and tumor accumulation.

Extracellular vesicles (EVs) are future promising therapeutics, but their instability in vivo after administration remains an important barrier to their further development. Many groups evaluated EV surface modification strategies to add a targeting group with the aim of controlling EV biodistribution. Conversely, fewer groups focused on their stabilization to obtain "stealth" allogenic EVs. Modulating their stabilization and biodistribution is an essential prerequisite for their development as nano-therapeutics. Here, we explored polyoxazolines with lipid anchors association to the EV membrane (POxylation as an alternative to PEGylation) to stabilize EVs in plasma and control their biodistribution, while preserving their native properties. We found that this modification maintained and seemed to potentiate the immunomodulatory properties of EVs derived from mesenchymal stem/stromal cells (MSC). Using a radiolabeling protocol to track EVs at a therapeutically relevant concentration in vivo, we demonstrated that POxylation is a promising option to stabilize EVs in plasma because it increased EV half-life by 6 fold at 6 h post-injection. Moreover, EV accumulation in tumors was higher after POxylation than after PEGylation.

Isolation and Characterization of Extracellular Vesicles to Activate Retina Regeneration.

Mammals do not possess the ability to spontaneously repair or regenerate damaged retinal tissue. In contrast to teleost fish which are capable of retina regeneration through the action of Müller glia, mammals undergo a process of reactive gliosis and scarring that inhibits replacement of lost neurons. Thus, it is important to discover novel methods for stimulating mammalian Müller glia to dedifferentiate and produce progenitor cells that can replace lost retinal neurons. Inducing an endogenous regenerative pathway mediated by Müller glia would provide an attractive alternative to stem cell injections or gene therapy approaches. Extracellular vesicles (EVs) are now recognized to serve as a novel form of cell-cell communication through the transfer of cargo from donor to recipient cells or by the activation of signaling cascades in recipient cells. EVs have been shown to promote proliferation and regeneration raising the possibility that delivery of EVs could be a viable treatment for visual disorders. Here, we provide protocols to isolate EVs for use in retina regeneration experiments.

Stem Cell-Derived Exosomes as a Therapeutic Option for Spinal Cord Injuries; a Systematic Review and Meta-Analysis.

Introduction: Exosomes function as cell signaling carriers and have drawn much attention to the cell-free treatments of regenerative medicine. This meta-analysis aimed to investigate the efficacy of mesenchymal stem cell-derived (MSC-derived) exosomes in animal models of spinal cord injuries (SCI). Method: A comprehensive search was conducted in Medline, Embase, Scopus, and Web of Science to attain related articles published by January 31, 2023. The eligible keywords were correlated with the spinal cord injury and MSC-derived exosomes. The evaluated outcomes were locomotion, cavity size, cell apoptosis, inflammation, neuro-regeneration, and microglia activation. A standardized mean difference was calculated for each sample and a pooled effect size was reported. Results: 65 papers fully met the inclusion criteria. Treatment with MSC-derived exosomes ultimately improved locomotion and shrunk cavity size (p<0.0001). The administration of MSC-derived exosomes enhanced the expression of beta-tubulin III, NF200, and GAP-43, and increased the number of NeuN-positive and Nissl-positive cells, while reducing the expression of glial fibrillary acidic protein (p<0.0001). The number of apoptotic cells in the treatment group decreased significantly (p<0.0001). Regarding the markers of microglia activation, MSC-derived exosomes increased the number of CD206- and CD68-positive cells (p=0.032 and p<0.0001, respectively). Additionally, MSC-derived exosome administration significantly increased the expression of the anti-inflammatory interleukin (IL)-10 and IL-4 (p<0.001 and p=0.001, respectively) and decreased the expression of the inflammatory IL-1b, IL-6, and TNF-a (p<0.0001). Conclusion: MSC-derived exosome treatment resulted in a significantly improved locomotion of SCI animals through ameliorating neuroinflammation, reducing apoptosis, and inducing neuronal regrowth by facilitating a desirable microenvironment.

Exosomal let-7b-5p deriving from parietal epithelial cells attenuate renal fibrosis through suppression of TGFßR1 and ARID3a in obstructive kidney disease.

As renal progenitor cells, parietal epithelial cells (PECs) have demonstrated multilineage differentiation potential in response to kidney injury. However, the function of exosomes derived from PECs has not been extensively explored. Immunofluorescent staining of Claudin-1 was used to identify primary PECs isolated from mouse glomeruli. Transmission electron microscopy, nanoparticle tracking analysis, and western blotting were used to characterize the properties of PECs-derived exosomes (PEC-Exo). The therapeutic role of PEC-Exo in tubulointerstitial fibrosis was investigated in the unilateral ureteral obstruction (UUO) mouse model and TGF-ß1-stimulated HK-2 cells. High-throughput miRNA sequencing was employed to profile PEC-Exo miRNAs. One of the most enriched miRNAs in PEC-Exo was knocked down by transfecting miRNA inhibitor, and then we investigated whether this candidate miRNA was involved in PEC-Exo-mediated tubular repair. The primary PECs expressed Claudin-1, PEC-Exo was homing to obstructed kidney, and TGF-ß1 induced HK-2 cells. PEC-Exo significantly alleviated renal inflammation and ameliorated tubular fibrosis both in vivo and in vitro. Mechanistically, let-7b-5p, highly enriched in PEC-Exo, downregulated the protein levels of transforming growth factor beta receptor 1(TGFßR1) and AT-Rich Interaction Domain 3A(ARID3a) in tubular epithelial cells (TECs), leading to the inhibition of p21 and p27 to restoring cell cycle. Furthermore, administration of let-7b-5p agomir mitigated renal fibrosis in vivo. Our findings demonstrated that PEC-derived exosomes significantly repressed the expression of TGFßR1 and ARID3a by delivering let-7b-5p, thereby alleviating renal fibrosis. This study provides novel insights into the role of PEC-Exo in the repair of kidney injury and new ideas for renal fibrosis intervention.

Research progress of exosomes from different sources in myocardial ischemia.

Ischemic heart disease refers to the imbalance between the supply and demand of myocardial blood; it has various causes and results in a class of clinical diseases characterized by myocardial ischemia (MI). In recent years, the incidence of cardiovascular disease has become higher and higher, and the number of patients with ischemic heart disease has also increased year by year. Traditional treatment methods include drug therapy and surgical treatment, both of which have limitations. The former maybe develop risks of drug resistance and has more significant side effects, while the latter may damage blood vessels and risk infection. At this stage, a new cell-free treatment method needs to be explored. Many research results have shown that exosomes from different cell sources can protect the ischemic myocardium via intercellular action methods, such as promoting angiogenesis, inhibiting myocardial fibrosis, apoptosis and pyroptosis, and providing a new basis for the treatment of MI. In this review, we briefly introduce the formation and consequences of myocardial ischemia and the biology of exosomes, and then focus on the role and mechanism of exosomes from different sources in MI. We also discuss the role and mechanism of exosomes pretreated with Chinese and Western medicines on myocardial ischemia. We also discuss the potential of exosomes as diagnostic markers and therapeutic drug for MI.

Human bone marrow mesenchymal stem cell-derived exosomes loaded with gemcitabine inhibit pancreatic cancer cell proliferation by enhancing apoptosis.

BACKGROUND: Pancreatic cancer remains one of the most lethal malignancies, and has limited effective treatment. Gemcitabine (GEM), a chemotherapeutic agent, is commonly used for clinical treatment of pancreatic cancer, but it has characteristics of low drug delivery efficiency and significant side effects. The study tested the hypothesis that human bone marrow mesenchymal stem cell (MSC)-derived exosomes loaded with GEM (Exo-GEM) would have a higher cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis. AIM: To investigate the cytotoxicity of MSC-derived Exo-GEM against pancreatic cancer cells in vitro. METHODS: Exosomes were isolated from MSCs and characterized by transmission electron microscopy and nanoparticle tracking analysis. Exo-GEM through electroporation, sonication, or incubation, and the loading efficiency was evaluated. The cytotoxicity of Exo-GEM or GEM alone against human pancreatic cancer Panc-1 and MiaPaca-2 cells was assessed by MTT and flow cytometry assays. RESULTS: The isolated exosomes had an average size of 76.7 nm. The encapsulation efficacy and loading efficiency of GEM by electroporation and sonication were similar and significantly better than incubation. The cytotoxicity of Exo-GEM against pancreatic cancer cells was stronger than free GEM and treatment with 0.02 µM Exo-GEM significantly reduced the viability of both Panc-1 and MiaPaca-2 cells. Moreover, Exo-GEM enhanced the frequency of GEM-induced apoptosis in both cell lines. CONCLUSION: Human bone marrow MSC-derived Exo-GEM have a potent cytotoxicity against human pancreatic cancer cells by enhancing their apoptosis, offering a promising drug delivery system for improving therapeutic outcomes.

Exosome-loaded biomaterials for tendon/ligament repair.

Exosomes, a specialised type of extracellular vesicle, have attracted significant attention in the realm of tendon/ligament repair as a potential biologic therapeutic tool. While the competence of key substances responsible for the delivery function was gradually elucidated, series of shortcomings exemplified by the limited stability still need to be improved. Therefore, how to take maximum advantage of the biological characteristics of exosomes is of great importance. Recently, the comprehensive exploration and application of biomedical engineering has improved the availability of exosomes and revealed the future direction of exosomes combined with biomaterials. This review delves into the present application of biomaterials such as nanomaterials, hydrogels, and electrospun scaffolds, serving as the carriers of exosomes in tendon/ligament repair. By pinpointing and exploring their strengths and limitations, it offers valuable insights, paving the way the future direction of biomaterials in the application of exosomes in tendon/ligament repair in this field.

Reference gene panel for urinary exosome-based molecular diagnostics in patients with kidney disease.

BACKGROUND: Kidney disease is a severe complication of diabetes that often leads to end-stage renal disease. Early diagnosis is crucial for prevention or delay. However, the current diagnostic methods, with their limitations in detecting the disease in its early stages, underscore the urgency and importance of finding new solutions. miRNAs encapsulated inside urinary exosomes (UEs) have potential as early biomarkers for kidney diseases. The need for reference miRNAs for accurate interpretation currently limits their translational potential. AIM: To identify consistently expressing reference miRNAs from UEs of controls and patients with type 2 diabetesmellitus (T2DM) and biopsy-confirmed kidney diseases. METHODS: miRNA profiling was performed on UEs from 31 human urine samples using a rigorous and unbiased method. The UEs were isolated from urine samples collected from healthy individuals (n = 6), patients with T2DM (n = 13), and T2DM patients who also had kidney diseases (including diabetic nephropathy, n = 5; membranous nephropathy, n = 5; and IgA nephropathy, n = 2) through differential ultracentrifugation. After characterizing the UEs, miRNA expression profiling using microarray technology was conducted. RESULTS: Microarray data analysis identified 14 miRNAs that were consistently expressed in UEs from 31 human samples, representing various kidney conditions: diabetic controls, diabetic nephropathy, membrane nephropathy, IgA nephropathy, and healthy controls. Through in silico analysis, we determined that 10 of these miRNAs had significant potential to serve as reference genes in UEs. CONCLUSION: We identified uniformly expressing UE miRNAs that could serve as reference genes kidney disease biomarkers.

Mesenchymal stem cells in wound healing: A bibliometric analysis as a powerful research tool.

Bibliographic analysis is still very rarely used in experimental basic study papers. The comprehensive bibliometric analysis of scientific literature on research progress and challenges in stem cell therapy for diabetic chronic wounds, which was conducted in the work of Shi et al can be a case study and a source of valuable information for writing reviews and experimental papers in this field. Basic experimental studies on a role of mesenchymal stem cells (MSCs) in wound healing that are published in 2023-2024, such as Zhang et al in 2023, Hu et al in 2023, Wang et al in 2023 are certainly also subjects for applying this powerful tool to analyze current research, challenges and perspectives in this field. This is due to the fact that these studies have addressed a great variety of aspects of the application of MSCs for the treatment of chronic wounds, such as using both the cells themselves and their various products: Sponges, hydrogels, exosomes, and genetic constructions. Such a wide variety of directions in the field of study and biomedical application of MSCs requires a deep understanding of the current state of research in this area, which can be provided by bibliometric analysis. Thus, the use of such elements of bibliographic analysis as publication count by year and analysis of top-10 keywords calculated independently or cited from bibliometric analysis studies can be safely recommended for every basic study manuscripts, primarily for the "Introduction" section, and review.

Suppression of certain intestinal microbiota metabolites may lead to gestational diabetes in mice fed a high-fat diet.

Background: We aim to establish a gestational diabetes mellitus (GDM) mouse model with mice fed with a high-fat diet (HFD) in comparison with pregnant mice with normal blood glucose levels to investigate the role of intestinal microbiota in the development of HFD-induced GDM. Methods: We divided healthy 6-week-old female C57BL mice into an HFD-induced GDM group and a normal diet group. Their bacterial flora and metabolites in intestinal fecal exosomes were co-analyzed using 16 s multi-region sequencing and compared. Findings: Alpha (α) diversity was lower within the model group compared to the control group. Beta (ß) diversity was significantly different between the two groups. The relative abundances of Lactobacillus, Actinomyces, Rothia, and Bacteroidetes were significantly different between the two groups. Fermentation and nitrate consumption were significantly higher in the GDM group. Multiple bacteria were associated with glycerophosphocholine, S-methyl-5'-thioadenosine, quinolinate, galactinol, deoxyadenosine, DL-arginine, and 2-oxoadenic acid. Interpretation: Imbalances in the production of Lactobacillus, Bacteroidetes, Actinomyces, and Rothia and their related metabolites may lead to metabolic disturbances in GDM. These indicators may be used to assess changes affecting the intestinal microbiota during pregnancy and thus help modulate diet and alter blood glucose.

Contribution of extracellular vesicles to steatosis-related liver disease and their therapeutic potential.

Extracellular vesicles (EVs) are small particles released by many cell types in different tissues, including the liver, and transfer specific cargo molecules from originating cells to receptor cells. This process generally culminates in activation of distant cells and inflammation and progression of certain diseases. The global chronic liver disease (CLD) epidemic is estimated at 1.5 billion patients worldwide. Cirrhosis and liver cancer are the most common risk factors for CLD. However, hepatitis C and B virus infection and obesity are also highly associated with CLD. Nonetheless, the etiology of many CLD pathophysiological, cellular, and molecular events are unclear. Changes in hepatic lipid metabolism can lead to lipotoxicity events that induce EV release. Here, we aimed to present an overview of EV features, from definition to types and biogenesis, with particular focus on the molecules related to steatosis-related liver disease, diagnosis, and therapy.

Exosome-mediated delivery of siRNA molecules in cancer therapy: triumphs and challenges.

The discovery of novel and innovative therapeutic strategies for cancer treatment and management remains a major global challenge. Exosomes are endogenous nanoscale extracellular vesicles that have garnered increasing attention as innovative vehicles for advanced drug delivery and targeted therapy. The attractive physicochemical and biological properties of exosomes, including increased permeability, biocompatibility, extended half-life in circulation, reduced toxicity and immunogenicity, and multiple functionalization strategies, have made them preferred drug delivery vehicles in cancer and other diseases. Small interfering RNAs (siRNAs) are remarkably able to target any known gene: an attribute harnessed to knock down cancer-associated genes as a viable strategy in cancer management. Extensive research on exosome-mediated delivery of siRNAs for targeting diverse types of cancer has yielded promising results for anticancer therapy, with some formulations progressing through clinical trials. This review catalogs recent advances in exosome-mediated siRNA delivery in several types of cancer, including the manifold benefits and minimal drawbacks of such innovative delivery systems. Additionally, we have highlighted the potential of plant-derived exosomes as innovative drug delivery systems for cancer treatment, offering numerous advantages such as biocompatibility, scalability, and reduced toxicity compared to traditional methods. These exosomes, with their unique characteristics and potential for effective siRNA delivery, represent a significant advancement in nanomedicine and cancer therapeutics. Further exploration of their manufacturing processes and biological mechanisms could significantly advance natural medicine and enhance the efficacy of exosome-based therapies.

Uptake of Mesenchymal Stem Cell-Derived Exosomes in Mouse Brain through Intranasal Delivery.

INTRODUCTION: Exosomes are nanoscale extracellular vesicles that widely participate in intercellular communication. An increasing number of studies have reported on the neuroprotective effects of stem cell-derived exosomes in brain diseases through various delivery methods. However, only a few reports are available on the delivery and uptake of stem cell-derived exosomes in the brains of mice of different ages. METHODS: PKH-26-labelled mesenchymal stem cell-derived exosomes were collected, and their uptake was investigated in the brains of mice aged 2 weeks, 2 months, and >6 months, 24 hours after intranasal delivery. RESULTS: No exosomes were distributed in the whole brains of 2-week-old mice after 24 hours of intranasal delivery. However, a small number of exosomes were found in the olfactory bulb, cortex, and hippocampus of 2-month-old mice, with no exosomes observed in the cerebellum. In contrast, a large number of exosomes were ingested in all brain regions, including the olfactory bulb, cortex, hippocampus, and cerebellum, of >6-month-old mice. CONCLUSION: Exosomes can enter the brains of adult mice through intranasal administration, but there are differences in the uptake rate among mice of different ages. These findings provide a theoretical basis for the future clinical administration of exosomes for treating brain disorders.

Titanium surfaces loaded with puerarin and exosomes derived from adipose stem cells promote the proliferation and differentiation of pre-osteoblasts.

The study is to evaluate the effects of collagen/hyaluronic acid coating with or without puerarin and exosomes (Exos) derived from adipose stem cells (ADSCs-Exos) on pre-osteoblast proliferation and differentiation on the surface of titanium materials. Titanium materials with different coatings were prepared by layer-by-layer technique, evaluating the surface characterization. Cell functions were assessed by cell biology experiments. Related genes and proteins were assessed by RT-qPCR and Western blot. Puerarin or ADSCs-Exos coating had better effects on promoting the adhesion, proliferation and differentiation of pre-osteoblasts, and the strongest effect was found after their co-coatings, manifesting as the up-regulations of alkaline phosphatase (ALP) activity, collagen type I alpha 1 (Col1a1), runt-related transcription factor 2 (Runx2), osterix and activating transcription factor-2 (ATF-2). Levels of phosphorylated-P38 (p-P38) and p-ATF-2 were up-regulated in pre-osteoblasts grown on puerarin and ADSCs-Exos-loaded titanium surfaces. Titanium surfaces loaded with puerarin and ADSCs-Exos promotes the proliferation and differentiation of pre-osteoblasts.

Identification of exosome-related gene features in psoriasis and construction of a diagnostic model via integrated bioinformatics analysis.

BACKGROUND: Psoriasis, a chronic inflammatory dermatosis, profoundly affects patients' well-being. Although exosomes are key in disease etiology, diagnostic potentials of associated genes are unclear. Our research targeted bioinformatics-based characterization of exosome-related genes and the development of a diagnostic model for psoriasis. METHODS: Within GSE30999 dataset, an exosome-centric diagnostic model was formulated. Its diagnostic capability was appraised in GSE30999 and GSE14905 cohorts. Human keratinocytes (HaCaT) were used to construct psoriasis cell model. qRT-PCR was used to detect expression of diagnostic genes in the model. Construction of a protein-protein interaction network was undertaken, complemented by enrichment analyses. Comparative evaluation of immunological microenvironments between healthy controls and disease cohort was executed. Prospective miRNAs and transcription factors (TFs) were prognosticated using online prediction tools. RESULTS: A distinctive diagnostic model with superior diagnostic performance, evidenced by an AUC value greater than 0.88, was unveiled. The model featured seven exosome-related biomarker genes (CCNA2, NDC80, CCNB1, CDCA8, KIF11, CENPF, and ASPM) interwoven in a complex network and chiefly linked in the regulation of Cell Cycle and Cellular Senescence. These genes were significantly overexpressed in psoriasis cell models. Immune infiltration analysis distinguished profound discrepancies (p < 0.05) in immunological microenvironment between disease and control groups with enrichment of T cells CD4 memory activated, Macrophages M1, and Neutrophils in the disease group. 11 miRNAs and 27 TFs were identified. CONCLUSION: The study introduces a new and potent diagnostic model for psoriasis, with selection of credible exosome-associated biomarker genes. These discoveries aid in clinical diagnostics and research on exosome involvement in psoriasis.

Exosomal therapy is a luxury area for regenerative medicine.

Stem cell-based therapies have made significant advancements in tissue regeneration and medical engineering. However, there are limitations to cell transplantation therapy, such as immune rejection and limited cell viability. These limitations greatly impede the translation of stem cell-based tissue regeneration into clinical practice. In recent years, exosomes, which are packaged vesicles released from cells, have shown promising progress. Specifically, exosomes derived from stem cells have demonstrated remarkable therapeutic benefits. Exosomes are nanoscale extracellular vesicles that act as paracrine mediators. They transfer functional cargos, such as miRNA and mRNA molecules, peptides, proteins, cytokines, and lipids, from MSCs to recipient cells. By participating in intercellular communication events, exosomes contribute to the healing of injured or diseased tissues and organs. Studies have shown that the therapeutic effects of MSCs in various experimental paradigms can be solely attributed to their exosomes. Consequently, MSC-derived exosomes can be modified and utilized to develop a unique cell-free therapeutic approach for treating multiple diseases, including neurological, immunological, heart, and other diseases. This review is divided into several categories, including the current understanding of exosome biogenesis, isolation techniques, and their application as therapeutic tools.

A noninvasive method of diagnosing membranous nephropathy using exosomes derived from urine.

Background: Membranous nephropathy (MN) is a specific autoimmune disease affecting kidneys. It is characterized by the accumulation of immune complexes in the glomerular basement membrane. Renal biopsy is currently the standard procedure to confirm the diagnosis, although the presence of autoantibodies against the phospholipase A2 receptor (PLA2R) can also help diagnose. In this study, we aimed to investigate the potential of urinary exosomes as noninvasive markers for diagnosing MN. Methods: Exosomes were extracted from urine samples of five patients with MN and four healthy controls. The concentration of PLA2R was measured in both urine and isolated exosomes using enzyme-linked immunosorbent assay techniques. The measurements were adjusted based on the urine creatinine (UCr) level of each participant. Results: The levels of PLA2R/UCr were investigated in urine and urine-derived exosomes from patients and controls. Results of the analysis revealed significantly higher expression of PLA2R/UCr in patients compared to the control group (p < 0.05). Furthermore, the expression level of PLA2R/UCr was higher in urine-derived exosomes than in urine samples. Additionally, a positive correlation was observed between the expression levels of PLA2R/UCr and the urine protein-to-creatinine ratio, with urine-derived exosomes exhibiting a stronger correlation than urine samples. Conclusion: Studies have indicated that measuring exosomal PLA2R/UCr levels in urine could be a noninvasive method for diagnosing MN. Using urine-derived exosomes could also reduce the burden of performing a biopsy on patients and facilitate follow-up treatment, such as monitoring for future recurrence.

Role of bone marrow mesenchymal stem cell-derived exosomes in reducing neurotoxicity and depression-like behaviors induced by doxorubicin in rats.

Background: Doxorubicin (DOX) is a broad-spectrum antitumor drug while its use is limited nowadays due to its neurobiological side effects associated with depression. Bone marrow mesenchymal stem cells (BM-MSCs) derived exosomes are a promising regenerative therapy. In this study, we investigated the therapeutic potentiality of BM-MSCs derived exosomes against the neurotoxicity induced by DOX. Methods: Twenty-four male albino rats were divided equally in to three groups as follow: group 1 (control), group 2 (rats injected intraperitoneally (i.p|) with DOX at a dose 2.5mg/Kg), and group 3 (rats injected with DOX and BM-MSCs derived exosomes i.p at a dose 1.5ml/Kg). During the experiment the behavior tests were noted, after three weeks rats were sacrificed, serum and brain samples were collected for biochemical, molecular and histopathological examinations. Results: The results revealed that DOX causing impairment of the locomotor and increasing the anxiety like behavior of rats, marked neuropathological changes, significant elevation of MDA content and TNF-α concentration, reduction of phospholipase (PLD) and acetylcholinesterase (AChE) protein concentration in addition, there were up regulation of JNK, NF-κB and p38 genes and down regulation of Erk1. Conclusion: Exosomal therapy improved the substantial neurotoxicity of DOX through modulating the markers involved in the neurotoxic signalling pathway of DOX that resulting in improving the pathological lesions and the animal behaviours.

Intestinal flora and bile acid interactions impact the progression of diabetic kidney disease.

In recent years, with the rapid development of omics technologies, researchers have shown that interactions between the intestinal flora and bile acids are closely related to the progression of diabetic kidney disease (DKD). By regulating bile acid metabolism and receptor expression, the intestinal flora affects host metabolism, impacts the immune system, and exacerbates kidney injury in DKD patients. To explore interactions among the gut flora, bile acids and DKD, as well as the related mechanisms, in depth, in this paper, we review the existing literature on correlations among the gut flora, bile acids and DKD. This review also summarizes the efficacy of bile acids and their receptors as well as traditional Chinese medicines in the treatment of DKD and highlights the unique advantages of bile acid receptors in DKD treatment. This paper is expected to reveal a new and important potential strategy for the clinical treatment of DKD.