Table 2 Studies on the clinical relevance of exosomal-derived miRNA and protein biomarkers in lung cancer

EGFR

Lung Tissue biopsy

Ultracentrifugation and Flow cytometry western blotting

Therapy monitoring and diagnosis

30 NSCLC + 10 with chronic lung inflammation

Approximately 80% of exosomes isolated from LC biopsies contained EGFR. These purified exosomes suppressed CD8 + T cells specific to tumor antigens by regulatory T cells suggesting that EGFR-containing exosomes may promote immunological tolerance in lung cancer, which has ramifications for immunotherapy methods

[111]

NY-ESO-1, EGFR, PLAP, and Alix

Plasma

Extracellular Vesicle Array

Prognosis

276 NSCLC

NY-ESO-1 was linked to a lower overall survival rate, indicating its potential as a robust prognostic biomarker in NSCLC

[159]

CD151, CD171, Tetraspanin 8

Plasma

Extracellular Vesicle Array

Diagnosis

336 LC + 126 C

Exosomal proteins CD151, CD171, and tetraspanin- 8 exhibited the greatest capacity to differentiate between cancer patients with varying histological subtypes, indicating that profiling of exosome proteins has the potential to be a dependable diagnostic method for lung cancer, regardless of the subtype or stage of the disease

[66]

CDL5, C20ORF3, CLEC3B, SAA4, SERFINC1, and LSERFINF1

Serum

Polyethylene glycol-based precipitation and immunoaffinity separation- and western blot

Diagnosis

20 AC + 20 SCLC + 20 SCC + 20 C

Expression of exosomal CD5L was observed to correlate with the expression of cancer tissue, implying that it may function as a potential biomarker for the non-invasive diagnosis of lung cancer through liquid biopsy

[162]

LRG-1

Urine

Ultracentrifugation and transmission electron microscopy

Diagnosis

8 NSCLS + 10 C

LRG1 mRNA was elevated in NSCLC patients' urine exosomes and lung tissue, suggesting its promise as a diagnostic for non-invasive NSCLC detection

[7]

Panel array of 30 protein

Plasma

Extracellular Vesicle Array

Diagnosis

109 NSCLC + 110 C

Using EV Array analysis, exosomes were detected and characterized in all samples. Through multivariate analysis using the Random Forests method, a model consisting of 30 markers was generated, which successfully distinguished the NSCLC patients with controls

[4]

PD-L1

Plasma

Ultracentrifugation

Diagnosis and prognosis

51 NSCLC

In patients with advanced NSCLC, the increased expression of PD-L1 mRNA, exoPD-L1, or both during the initial stage of ICIs treatment may serve as potential indicators of positive biomarkers for enhanced effectiveness and overall survival

[167]

TIM-3

Galectin-9

Plasma

precipitation, western blotting and TEM

Diagnosis

103 NSCLC

56 C

Tim-3 and Galectin-9 levels were considerably higher in the plasma of NSCLC patients than in controls. Moreover, they were positively associated with various malignant characteristics such as larger tumor size, advanced stages, and distant metastasis, suggesting their potential use as biomarkers for NSCLC

[166]

miR-30e-3p, miR-361-5p, miR-10b-5p miR-181-5p, miR-30a-3p, miR-15b-5p, and miR-320b

Plasma

Ultracentrifugation

Early diagnosis and histological classification of different cancer types

Set 1. 16AC + 10SSC + 12C

Set2

10AC + 10SSC + 30C

Symptomatic = 60

Next-generation sequencing revealed the presence of adenocarcinoma-specific miRNAs and SCC-specific miRNAs in TEXs suggesting their potential as effective and sensitive biomarkers for early NSCLC detection without invasive procedures

[168]

hsa-miR-210-5p hsa-miR-9-3p, hsa-miR-205-5p,, and hsa-miR-1269a

Serum

Precipitation

Diagnosis and prognosis

147 NSCLC + 149 C

NSCLC patients had higher levels of specific micro-RNAs in serum exosomes. The study also found that miR-1269a promotes proliferation, migration and invasion in NSCLC cells

[169]

miR-378a, miR-379, miR-139-5p, and miR-200b-5p

miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100, and miR-154-3p

Plasma

Precipitation

Diagnosis

10AC + 10LG + 10C

The miR-378a, miR-379, miR-139-5p and miR-200b-5p varied significantly between lung adenocarcinomas and carcinomas compared to non-nodule samples obtained from healthy former smokers. On the other hand, miR-151a-5p, miR-30a-3p, miR-200b-5p, miR-629, miR-100 and miR-154-3p could distinguish between lung adenocarcinoma and granuloma based on their expression levels

[170]

miR-378i, miR-205-5p, and miR-200b

Pleural effusion

Ultracentrifugation

Diagnosis and histological classification

9 lung cancer + 

9 pneumonia + 

9 tuberculosis

The study found that miR-378i, miR-205-5p and miR-200b were expressed differently in the samples analyzed. Specifically, these miRNAs were differentially expressed in lung cancer samples, while 27 other miRNAs were differentially expressed between pneumonia and tuberculosis groups. Of note, miR-205-5p and miR-200b were significantly increased only in the lung cancer group

[171]

miR-182 and miR-210

Pleural effusion

Precipitation

Diagnosis

41 AC + 15 benign pleural effusion

The expression of miR-182 and miR-210 was significantly greater in lung adenocarcinoma samples compared to malignant pleural effusion samples. These miRNAs may serve as biomarkers to differentiate between lung adenocarcinoma and malignant pleural effusion

[172]

miR-200 and LCN2

pleural effusions

Precipitation

RNA profiling

Differential diagnosis

18 AC + 18 benign inflammatory processes

Analysis of miRNA carried by exosomes in pleural effusions can potentially differentiate individuals with benign conditions from those with lung adenocarcinoma. miR-200 microRNAs and LCN2 could be useful diagnostic markers for detecting lung cancer through liquid biopsies

[173]

miR-21 and miR-4257

Plasma

Ultracentrifugation and transmission electron microscopy

Histological classification and prognosis

6 NSCLC + 129 stage 1 + 34 stage II + 32 Stage III + 30 C

Patients with non-small cell lung cancer who had higher amounts of miR-21 and miR-4257 in their plasma exosomes had a lower risk of dying from their illness. These miRNAs may one day be used as an indicator that can forecast whether or not NSCLC recurrence will occur

[174]

miR-23b-3p, miR-10b-5p and miR-21-5p

Plasma

Precipitation and Transmission electron microscopy, western blot

Diagnosis and prognosis

10 AC + 10 C

Elevated levels of miR-23b-3p, miR-10b-5p, and miR-21-5p were linked to poorer overall survival outcomes, according to independent studies of exosomes. The use of plasma exosomal miR-23b-3p, miR-10b-5p, and miR-21-5p may be a reliable non-invasive way to forecast the prognosis of NSCLC patients

[175]

miR-20b-5p and miR-3187-5p

Serum

Ultracentrifugation

Diagnosis and prognosis

330 NSCLC + 312 C

miR-20b-5p and miR-3187-5p present in circulating serum exosomes are potential candidates as NSCLC biomarkers

[176]

let-7a-5p and BCL2L1

Serum

Ultracentrifugation

Diagnosis and prognosis

154 LC + 54 pneumoconiosis + 100C

The reduced exosomal let-7a-5p expression and increased BCL2L1 expression in patients with lung adenocarcinoma can be predictive biomarkers for poor survival outcomes

[177]

miR-382

Serum

Precipitation

Diagnosis

126 NSCLC + 60 C

NSCLC patients showed a significant reduction in circulating exosomal miR-382 levels, which increased after one month of surgical resection. The decreased levels of circulating exosomal miR-382 were linked with unfavorable clinical outcomes and lower overall survival rates. Serum exosomal miR-382 was identified as an independent prognostic factor for overall survival in cases of NSCLC

[178]

eIF4E

Serum

Precipitation and western blotting

Prognosis

99 NSCLC + 40 C

Higher levels of eIF4E in NSCLC tissues were associated with advanced stages of the disease and poorer overall survival rates. In the NSCLC group, exosomal eIF4E expression in the serum of individuals with advanced TNM stage, distant metastasis, and CYFRA 21–1 was significantly higher compared to that of healthy individuals

[179]

miR-146a-5p

Serum

Precipitation and Transmission electron microscopy

Diagnosis

100 NSCLC

The exosomal miR-146a-5p found in the serum has the potential to act as a new biomarker for anticipating the efficacy of cisplatin treatment in patients with NSCLC. Furthermore, it can also be utilized for the continuous monitoring of drug resistance in real-time

[180]

miR-1169 and miR-260

Plasma

Diagnosis

Exosomal miR-1169 and miR-260 have been identified as potential biomarkers with distinct properties that can differentiate between NSCLC patients with wild-type EGFR and those with mutant EGFR during the early stages of the disease

[181]