hUC-MSC-Exosomes for T2DM - Safety & Efficacy (HOPE-T2DM)

Komparátor placeba: kontrolní skupina

Jiný: control group

active-comparator control：（n=16）The control group will receive an equal volume of the same buffer solution without exosomes (.Subjects in this groups will receive intravenous infusions once weekly for 8 weeks (a total of 8 doses)

Ostatní jména:

• active-comparator

Experimentální: exosomes treatment group

GoldenExo（NATX） treatment

Biologický: exosomes treatment group

GoldenExo（NATX） treatment group (n=32) The specific therapeutic dose for the second stage will be evaluated and determined jointly by the investigators and the Safety Monitoring Committee (SMC) after all three dose escalation trials (1×10¹¹, 3×10¹¹, 9×10¹¹ particles) in the first stage.Subjects in both groups will receive intravenous infusions once weekly for 8 weeks (a total of 8 doses).

Ostatní jména:

• GoldenExo（NATX） treatment group

Change in Glycated Hemoglobin (HbA1c)

The primary efficacy endpoint is the change in glycated hemoglobin (HbA1c) from baseline to Week 8. In the randomized comparative stage, between-group differences between the investigational intervention group and the control group will also be evaluated.

Unit of Measure: Percentage (%)

Interpretation:

Reflects long-term glycemic control and overall metabolic efficacy of the intervention.

Glycated Hemoglobin (HbA1c) Response Rate

Proportion of participants achieving HbA1c target control. Definition: HbA1c < 7.0% Unit of Measure: Percentage of participants (%)

Interpretation:

Reflects long-term glycemic target attainment rate.

Pancreatic Islet Function: Insulin (INS)

Comparison of serum/plasma insulin levels between baseline and various post-treatment follow-up time points via synchronous venous blood sampling at fasting.

Unit of Measure:Picomoles per liter (pmol/L). Interpretation:Used to evaluate circulating insulin levels. HOMA-IR assesses the sensitivity of peripheral target tissues (skeletal muscle, liver, adipose tissue) to insulin, where higher values indicate more severe resistance. HOMA-beta statically evaluates baseline pancreatic beta-cell secretory function under fasting conditions (applicable to subjects not receiving exogenous insulin therapy).

Pancreatic Islet Function: C-peptide

Comparison of serum/plasma C-peptide levels between baseline and various post-treatment follow-up time points, measured synchronously from venous blood at fasting.

Unit of Measure:Nanograms per milliliter (ng/mL) Interpretation:Used to evaluate endogenous insulin secretion. Because C-peptide bypasses hepatic first-pass metabolism, it precisely mirrors true residual endogenous pancreatic beta-cell mass and functional capacity. An increase from baseline (positive change) indicates functional recovery or preservation of pancreatic beta-cells.

Changes in Blood Glucose during MMTT

Fasting (0 min) and 2-hour postprandial (120 min) blood glucose levels are measured during mixed-meal tolerance test (MMTT). Changes from baseline at various post-treatment follow-up time points are compared.

Unit of Measure: mmol/L Interpretation: Lower postprandial glucose levels and/or reduced glucose excursion during MMTT indicate improved glycemic control and β-cell function.

Anthropometric and Metabolic Parameters

Assessment of body composition and metabolic status. Body Mass Index (kg/m²)

Interpretation:

Reflects systemic metabolic control and cardiometabolic risk profile.

Soluble Adhesion Molecule (sICAM-1)

Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1) as a marker of endothelial activation.

Unit of Measure: ng/mL

Interpretation:

Reflects endothelial dysfunction and vascular inflammatory activity.

Ophthalmologic Assessment

Assessment of diabetic retinopathy using fundus photography and standardized grading.

Unit of Measure: Clinical staging 5, listed below

Interpretation:

Reflects progression or stabilization of retinal microvascular disease.

1. No apparent retinopathy / No diabetic retinopathy (No DR)
2. Mild non-proliferative diabetic retinopathy (Mild NPDR)
3. Moderate non-proliferative diabetic retinopathy (Moderate NPDR)
4. Severe non-proliferative diabetic retinopathy (Severe NPDR)
5. Proliferative diabetic retinopathy (PDR)

Change in Central Obesity: Waist-to-Hip Ratio (WHR)

Evaluation of changes in waist and hip circumferences to calculate the Waist-to-Hip Ratio (WHR), comparing baseline measurements with various post-treatment follow-up time points to quantify central obesity (visceral fat accumulation).

Unit of Measure:Centimeters (cm) for raw circumferences; Ratio is dimensionless. (Normal reference range: Male < 0.9, Female < 0.85) .

Interpretation:A classic anthropometric clinical index for assessing visceral adiposity. A decrease from baseline (negative change) indicates targeted reduction in abdominal fat and metabolic risk alleviation.

Body fat percentage (%)

Comparison of the body fat percentage between baseline and various post-treatment follow-up time points to evaluate quantitative and qualitative shifts in overall body composition. Normal reference range: Male （10%~20%）, Female （20%~30%） Unit of Measure:Percentage (%) Interpretation:Used to differentiate whether total body weight fluctuations stem from a true reduction in adipose tissue mass or the unintended, unorganized loss of lean muscle mass. A decrease from baseline (negative change) represents a favorable structural metabolic improvement.

C-Reactive Protein (CRP)

Description: Comparative monitoring of systemic immune cell populations (leukocyte subsets) and C-Reactive Protein (CRP) absolute concentrations between baseline and post-treatment points.

Unit of Measure:Milligrams per liter (mg/L) (Note: Units to be finalized based on specific laboratory assay methods and markers selected).

Interpretation:Tracks acute infectious episodes, systemic clinical flare-ups, or subclinical active inflammatory processes relative to baseline safety thresholds.

Time in Range (TIR, 3.9-10.0 mmol/L)

Description:

Continuous glucose monitoring (CGM) is used to assess 24-hour interstitial glucose dynamics Unit of Measure: % (TIR)

Interpretation:

Reflects short-term glycemic stability and variability control.

Mean glucose level

Description:

Continuous glucose monitoring (CGM) is used to assess 24-hour interstitial glucose dynamics Unit of Measure: mmol/L

Interpretation:

Reflects short-term glycemic stability and variability control.

Coefficient of variation (CV%)

Continuous glucose monitoring (CGM) is used to assess 24-hour interstitial glucose dynamics Unit of Measure: %

Interpretation:

Reflects short-term glycemic stability and variability control.

Inflammatory Biomarkers：Interleukin-4 (IL-4)

A classic Th2-type anti-inflammatory cytokine modulating adaptive immune differentiation. Longitudinal alterations in serum IL-4 values will be evaluated using multiplex assays to assess Th2 immune response and inflammation alleviation effect.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Moderate IL-4 expression balances Th1/Th2 immune axis and suppresses excessive pro-inflammatory reaction. Declined IL-4 level leads to immune imbalance and aggravated inflammatory progression.

Unit of Measure: pg/mL

Interpretation:

Reflects systemic low-grade inflammation and immune modulation.

Inflammatory Biomarkers：Interleukin-6（ IL-6）

A multifunctional pleiotropic pro-inflammatory cytokine linking innate and adaptive immunity. Longitudinal alterations in serum IL-6 values will be evaluated using multiplex assays to monitor dynamic systemic inflammatory fluctuation and therapeutic inflammatory improvement.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Serum IL-6 concentration is positively correlated with the severity of systemic low-grade inflammation. Persistently elevated IL-6 facilitates inflammatory cell aggregation and chronic tissue pathological remodeling.

Inflammatory Biomarkers：Interleukin- 1β (IL-1β)

An early activated pro-inflammatory cytokine released by activated macrophages. Longitudinal alterations in serum IL-1β values will be evaluated using multiplex assays to assess the initiation degree of upstream inflammatory signaling pathways.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Elevated IL-1β triggers downstream cascade inflammatory activation, induces systemic inflammatory pain and tissue degeneration, and indicates active early low-grade inflammatory stimulation.

Inflammatory Biomarkers：Interleukin-10 (IL-10)

A pivotal anti-inflammatory cytokine secreted mainly by regulatory T cells and macrophages. Longitudinal alterations in serum IL-10 values will be evaluated to assess endogenous anti-inflammatory capacity and intervention-induced immune negative regulation.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Physiologically elevated IL-10 inhibits overactivated inflammatory cascade and reduces tissue inflammatory damage. Insufficient serum IL-10 expression breaks immune homeostasis, exacerbates systemic low-grade inflammation, and prolongs inflammatory pathological status.

Inflammatory Biomarkers：Interleukin-8 (IL-8)

A potent chemotactic pro-inflammatory cytokine targeting neutrophil migration. Longitudinal alterations in serum IL-8 values will be evaluated using multiplex assays to assess local and systemic inflammatory cell recruitment level.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Increased IL-8 induces massive inflammatory cell infiltration into tissues, amplifies local inflammatory lesions, and maintains chronic persistent low-grade inflammatory status in vivo.

Inflammatory Biomarkers：Interleukin-2 (IL-2)

A key lymphocyte-derived pro-inflammatory cytokine regulating T-cell proliferation and activation. Longitudinal alterations in serum IL-2 values will be evaluated using multiplex assays to assess peripheral T lymphocyte immune activation status.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Abnormally elevated IL-2 mediates excessive effector T-cell activation, enhances inflammatory immune attack, and participates in the occurrence and development of immune-mediated inflammatory lesions

Inflammatory Biomarkers：Tumor Necrosis Factor-alpha (TNF-α)

A core pro-inflammatory cytokine derived from monocytes and macrophages. Longitudinal alterations in serum TNF-α values will be evaluated using multiplex assays to assess systemic inflammatory activation degree and inflammatory injury level.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Sustained high serum TNF-α level drives persistent systemic low-grade inflammation, induces cellular apoptosis and visceral tissue damage, and acts as a key biomarker reflecting chronic inflammatory disease activity.

Inflammatory Biomarkers：Interferon-gamma (IFN-γ)

A typical type 1 pro-inflammatory cytokine produced by T lymphocytes and natural killer cells. Longitudinal alterations in serum IFN-γ values will be evaluated using multiplex assays to assess cellular immune activation and pro-inflammatory immune polarization.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Excess IFN-γ triggers Th1-type immune hyperactivation, promotes inflammatory cell infiltration, aggravates autoimmune and inflammatory responses, and predicts poor immune regulatory status.

Inflammatory Biomarkers：Interferon-alpha (IFN-α)

An innate immune-derived pro-inflammatory interferon primarily secreted by plasmacytoid dendritic cells. Longitudinal alterations in serum IFN-α values will be evaluated using multiplex assays to assess innate immune activation and early inflammatory response.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Upregulated IFN-α activates innate immune cascade reaction, induces systemic inflammatory cascade, and is closely associated with chronic low-grade inflammation and immune overreaction.

Inflammatory Biomarkers： Interleukin-17A（IL-17A）

A signature pro-inflammatory cytokine secreted by Th17 cells. Longitudinal alterations in serum IL-17A values will be evaluated using multiplex assays to assess Th17-mediated inflammatory response and mucosal inflammatory injury.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: High-level IL-17A breaks immune tolerance, promotes pro-inflammatory mediator release, and is a core biomarker for aggravated chronic inflammatory and autoimmune pathological changes.

Inflammatory Biomarkers：Interleukin-12p70 (IL-12p70)

A heterodimeric pro-inflammatory cytokine driving Th1 cell differentiation. Longitudinal alterations in serum IL-12p70 values will be evaluated using multiplex assays to assess Th1 immune axis differentiation bias.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Upregulated IL-12p70 polarizes immune response toward pro-inflammatory Th1 phenotype, amplifies cellular inflammatory immunity, and worsens systemic inflammatory imbalance.

Inflammatory Biomarkers：Interleukin-5 (IL-5)

A Th2-derived anti-inflammatory regulatory cytokine modulating eosinophil activity. Longitudinal alterations in serum IL-5 values will be evaluated using multiplex assays to assess type 2 immune regulation and inflammatory remission trend.

Unit of Measurement: Picograms per milliliter (pg/mL) Clinical Significance: Physiological IL-5 assists immune homeostasis maintenance and antagonizes excessive pro-inflammatory responses. Dysregulated IL-5 expression disrupts overall anti-inflammatory immune compensation in the body.

High-Density Lipoprotein Cholesterol (HDL-C)

Apolipoprotein A-I (ApoA-I) serves as its primary apolipoprotein. Longitudinal alterations in HDL-C values from baseline to each post-treatment follow-up time point will be evaluated to assess the modulation of lipid metabolism.

Unit of Measurement: Millimoles per liter (mmol/L) Clinical Significance: Within the physiological range, higher concentrations are clinically desirable. Conversely, a significantly reduced level (< 1.0 mmol/L) impairs the reverse cholesterol transport pathway, leading to a corresponding increase in cardiovascular and cerebrovascular risks.

Low-Density Lipoprotein Cholesterol (LDL-C)

Its primary pathophysiological function is to transport endogenous cholesterol from the liver to peripheral arterial walls. Variations from baseline to subsequent follow-up intervals will be analyzed to evaluate the systemic lipid metabolic profile.

Unit of Measurement: Millimoles per liter (mmol/L) Clinical Significance: LDL-C is established as the primary target for clinical lipid-lowering therapeutic interventions. Elevated levels accelerate cholesterol infiltration into the subendothelial space, driving atheromatous plaque formation and substantially escalating the risk of acute myocardial infarction and ischemic stroke.

Total Cholesterol (TC)

Description: TC represents the quantified sum of cholesterol contained within all circulating lipoprotein fractions. The numerical shifts between baseline and post-treatment follow-up points will be utilized to gauge the overall regulation of lipid homeostasis.

Unit of Measurement: Millimoles per liter (mmol/L) Clinical Significance: TC serves as a fundamental screening biomarker for macroeconomic cardiovascular risk assessment. A longitudinal reduction in TC levels relative to baseline denotes a favorable optimization of systemic lipid metabolism and a subsequent decrease in cardiovascular risk.

Triglycerides (TG)

Description: TG is derived primarily from exogenous dietary intake and endogenous hepatic synthesis. Post-treatment variations relative to baseline will be monitored across all specified follow-up time points to assess systemic lipid metabolic homeostasis.

Unit of Measurement: Millimoles per liter (mmol/L) Clinical Significance: A downward shift or a stabilized reduction from baseline values reflects a clinically meaningful improvement in systemic lipid metabolic status and a mitigation of metabolic syndrome severity.

Hepatic Fibrosis (LSM)

Liver stiffness is assessed using ultrasound elastography. Liver stiffness measurement (LSM) reflects the degree of hepatic fibrotic remodeling.

Unit of Measure: kPa Interpretation: Higher LSM values indicate more advanced liver fibrosis.

Hepatic Steatosis (CAP)

Liver fat content is assessed using ultrasound elastography. The Controlled Attenuation Parameter (CAP) reflects the degree of hepatic steatosis.

Unit of Measure: dB/m Interpretation: Higher CAP values indicate greater hepatic fat accumulation.

Carotid Atherosclerosis Assessment: Plaque Size

High-resolution vessel wall magnetic resonance imaging (HR-VWMRI) will be utilized to perform quantitative assessments of the target vascular plaque. Longitudinal variations in plaque metrics will be analyzed by evaluating the structural changes from baseline to each post-treatment follow-up time point.

Unit of Measurement: Millimeters (mm) Clinical Significance: A statistically significant reduction in plaque dimensions relative to baseline values serves as an objective indicator of plaque regression or reversal. This morphological regression (or reduction) denotes a favorable therapeutic response, an optimization of the local vascular microenvironment, and a subsequent mitigation of the overall vascular burden.

Carotid Atherosclerosis Assessment: Comparison of bilateral Carotid Intima-Media Thickness (CIMT)

Objectively evaluates macrovascular structural remodelling, atheromatous burden, and the progression or regression of systemic macrovascular sclerosis beyond isolated glycemic control.

Unit of Measurement: Millimeters (mm)

Urine Albumin-to-Creatinine Ratio (UACR)

Urine albumin-to-creatinine ratio (UACR) is a sensitive marker of early renal injury and a key indicator for diabetic kidney disease screening and progression monitoring. UACR is measured from spot urine samples (first-morning void preferred). Changes in UACR from baseline reflect the impact of the intervention on renal microvascular function Unit of Measure: mg/g Interpretation: Higher UACR values indicate greater urinary albumin excretion, reflecting more advanced renal damage.

Changes in Insulin Secretion during MMTT

Fasting (0 min) and 2-hour postprandial (120 min) insulin levels are measured during mixed-meal tolerance test (MMTT). Changes from baseline at various post-treatment follow-up time points are compared.

Unit of Measure: μIU/mL Interpretation: Enhanced postprandial insulin secretion indicates improved β-cell secretory function.

Changes in C-peptide Levels during MMTT

Fasting (0 min) and 2-hour postprandial (120 min) C-peptide levels are measured during mixed-meal tolerance test (MMTT). Changes from baseline at various post-treatment follow-up time points are compared. C-peptide is a more stable indicator of endogenous insulin secretion than insulin itself.

Unit of Measure: ng/mL Interpretation: Increased postprandial C-peptide levels indicate preserved or improved endogenous β-cell function.

Change in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR)

HOMA-IR is calculated from fasting blood glucose and fasting insulin (or fasting C-peptide as an alternative if patients are on an insulin regimen) to assess changes in insulin resistance from baseline to post-treatment follow-up time points.

Unit of Measure: Score on a scale (unitless) Interpretation: A lower HOMA-IR value indicates improved insulin sensitivity.

Change in Homeostatic Model Assessment for β-cell Function (HOMA-β)

HOMA-β is calculated from fasting blood glucose and fasting insulin (or fasting C-peptide as an alternative if patients are on an insulin regimen) to assess changes in pancreatic β-cell function from baseline to post-treatment follow-up time points.

Unit of Measure: Percentage (%) Interpretation: A higher HOMA-β value indicates improved β-cell function.

Diabetes Specific Quality of Life (DSQL)

Diabetes Specific Quality of Life Scale (DSQL) is a validated questionnaire assessing quality of life in patients with diabetes mellitus. The scale evaluates four domains: physiological function, psychological/spiritual, social relations, and treatment effects. Higher scores indicate poorer quality of life. DSQL is widely used in Chinese diabetic populations and has demonstrated good reliability and validity. The total score will be analyzed.

Unit of Measure：Score on a scale Interpretation: Higher scores indicate poorer quality of life.