Biomedicine & Pharmacotherapy 176 (2024) 116803

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Bibliometric and visualized analysis of the applications of exosomes based

drug delivery
Bohua Wei a, Haonan Huang b, Qian Cao c, *, Xiaoyu Song d, *, Zhichang Zhang e, *
a
School of Pharmacy, China Medical University, Shenyang, Liaoning Province 110122, China
b
China Medical University, Shenyang, Liaoning Province 110122, China
c
Department of cardiology, Shengjing hospital of China Medical University, Shenyang, Liaoning Province 110004, China
d
The College of Basic Medical Science, Health Sciences Institute, China Medical University, Shenyang, Liaoning Province 110122, China
e
Department of Computer, School of Intelligent Medicine, China Medical University, Shenyang, Liaoning Province 110122, China

A R T I C L E I N F O A B S T R A C T

Keywords: Exosomes, endogenous vesicles secreted by cells, possess unique properties like high biocompatibility, low
Exosome immunogenicity, targeting ability, long half-life, and blood-brain barrier permeability. They serve as crucial
Drug delivery intercellular communication vectors in physiological processes and disease occurrence. Our comprehensive
Citespace
analysis of exosome-based drug delivery research from 2013 to 2023 revealed 2,476 authors from 717 in­
Bibliometric
Mesenchymal stem cell
stitutions across 33 countries. Keyword clustering identified five research areas: drug delivery, mesenchymal
stem cells, cancer immunotherapy, targeting ligands, surface modifications, and macrophages. The combination
of exosome drug delivery technology with a proven clinical model enables the precise targeting of tumors with
chemotherapy or radiosensitising agents, as well as facilitating gene therapy. This bibliometric analysis aims to
characterize the current state and advance the clinical application of exosome-based drug delivery systems.

1. Introduction maintaining chondrocyte phenotypes, promoting extracellular matrix

synthesis, and enhancing chondrocyte migration. These actions facili­
Exosomes are extracellular vesicles with biofilm characteristics, that tate cartilage tissue repair and improve the joint environment [4].
are secreted by almost all cells with a particle size of 30–150 nm [1]. Moreover, through engineering modifications, ligands or targeting
Exosomes participate in physiological processes such as signal trans­ peptides can be fused to transmembrane protein genes expressed on the
mission and material transport in the body. Exosomes exhibit numerous exosome surface, resulting in engineered exosomes with targeted li­
advantages compared to artificially synthesized nanocarriers, including gands. These engineered exosomes enable targeted drug delivery ther­
superior biocompatibility, reduced immunogenicity, exceptional tar­ apy for tumors [5]. Additionally, exosomes facilitate drug delivery
geting capabilities, prolonged half-life, and the ability to traverse the across the blood-brain barrier, opening new possibilities for managing
blood-brain barrier. Kamerkar et al. have presented compelling evidence neurological conditions such as degenerative diseases, brain tumors, and
indicating that exosomes exhibit a significantly prolonged half-life in other brain disorders. Given their unique capabilities and versatility,
circulation and demonstrate a heightened affinity for targeting pancre­ exosomes are increasingly viewed as an active delivery system for
atic cancer tissues, compared to liposomes [2]. Alvarez-Erviti et al. clinical applications, promising to revolutionize the field of therapeutic
successfully employed exosomes derived from self-generated dendritic delivery.
cells to facilitate the delivery of siRNA to the brain, a task that has Bibliometrics is a mature research method in information science,
historically posed significant challenges for liposomes [3]. Exosomes, that has been proven to be an effective tool for studying the current
whether synthetic or cell-secreted, have garnered significant attention situation of the subject and predicting the development of the subject
for their potential in treating a range of medical conditions, including [6]. The application of bibliometrics enables the extraction of keywords,
cartilage tissue repair, tumors, and neurodegenerative diseases. Specif­ sources, authors, publication time and other information from the
ically, mesenchymal stem cell -derived exosomes (MSC-Exos) have literature. This information can then be integrated and correlated, and
exhibited regulatory effects on chondrocyte proliferation and apoptosis, the results of the analysis can be displayed intuitively using visual

* Corresponding authors.
E-mail addresses: cqdoc@163.com (Q. Cao), xysong@cmu.edu.cn (X. Song), zczhang@cmu.edu.cn (Z. Zhang).

https://doi.org/10.1016/j.biopha.2024.116803
Received 2 April 2024; Received in revised form 15 May 2024; Accepted 20 May 2024
Available online 23 May 2024
0753-3322/© 2024 The Author(s). Published by Elsevier Masson SAS. This is an open access article under the CC BY-NC license
(http://creativecommons.org/licenses/by-nc/4.0/).
B. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116803

methods. This approach is conducive to the interpretation of a great deal

of information and the mining of research hotspots [7]. The bibliometric
tools, including the R package "Bibliometrix" and software packages
such as "CiteSpace" and "VOSviewer", have gained extensive utilization
across diverse disciplines, such as medicine [8–11], information science
[12–15], environmental sciences ecology [16–19] and others. Initially,
exosomes were regarded as by-products of cellular metabolism. How­
ever, in 2013, a mechanism regulating the transport of vesicles,
including exosomes, was awarded the Nobel Prize for Medicine. This
research has also promoted a greater focus on exosomes. In recent de­
cades, the potential of exosomes as drug nanocarriers has garnered
significant research attention. Accumulating evidence indicates that
surface modification of exosomes to acquire targeted ligands can sub­
stantially enhance their targeting efficiency, positioning them as a
promising contender for the next generation of drug delivery vehicles.
Notably, their therapeutic prowess is particularly pronounced in the
realm of tumor immunotherapy. Despite these promising prospects,
several challenges hinder the clinical translation of exosome-based drug
delivery systems. These include the low yield of targeted exosomes, the
suboptimal efficiency of drug loading, and the rapid clearance of exo­
somes from circulation in vivo. Overcoming these obstacles is crucial for Fig. 1. Criteria and flowchart for inclusion and exclusion.
realizing the full therapeutic potential of exosome-mediated drug de­
livery. To gain a comprehensive understanding of the research trends 2.3. Bibliometric data analysis
and predict future development frontiers in exosomal drug delivery, this
study conducted a bibliometric analysis of relevant research published Bibliometric analysis was conducted using the bibliometrix package
between 2013 and 2023. By exploring the research directions and key (4.0.1) in the R software (4.2.2), VOSviewer (1.6.15.0) and CiteSpace
findings of the past decade, we aim to provide a valuable reference for (6.2.R5). We examined the following publication characteristics: coun­
researchers in this field and contribute to the early clinical application of tries/regions, journals, institutions, references, keywords, and the H-
exosome-carrying agents. By analyzing the evolution of research topics, index. The h-index is essentially an indicator that measures the regu­
identifying emerging trends, and predicting future directions, this study larity of a researcher’s scientific productivity and impact [20].
offers a critical assessment of the current status and future prospects of The text extraction function of VOSviewer (1.6.15.0) was used to
exosome-based drug delivery. We hope that our findings will inspire construct and visualize the co-occurrence network of significant lin­
further research and development in this promising field, ultimately guistic elements extracted from the scientific literature corpus [21]. The
leading to the successful translation of exosome-mediated drug delivery full counting mode was employed to analyze both organizations and
systems into clinical practice. journals [22]. For the analysis of organizations, the author type choice
as the co-author.
2. Materials and methods We extracted and analyzed key information from the downloaded
publications using RStudio V4.2.2 with the Bibliometrix package
2.1. Systemic search strategy installed [23]. The number and annual growth of publications are
summarized in the overview section; and journal information is
This study focuses on the utilization of exosomes in drug delivery extracted from the source section. Information about the countries was
systems, based on an extensive analysis of existing literature available in obtained from the author’s section. Information about the cited litera­
the Web of Science(WOS) database. On 3 January, 2024, we systemat­ ture is taken from the literature section. The extracted data were saved
ically searched the citation index of Web of Science Core Collections in the CSV format.
published between January 1, 2013 and December 31, 2023. To avoid CiteSpace is a visual analysis tool that integrates bibliometrics, data
this deviation, the document download process was expedited to ensure mining algorithms, and advanced visualization techniques to uncover
timely completion within 1 day(January 3, 2024). In this study, the latent knowledge embedded in the research literature [24]. With 3 years
search strategy was established as per the methodology employed: as a slice, the node type was selected as the term and reference for cluster
TS =( "exosome*" OR "exo*" OR "exosomal") AND TS=("drug carrier*" analysis, and the burst detection function was employed to identify
OR "drug loading" OR "drug delivery"). The Web of Science category was keywords with sudden increases in occurrence. Under the superimposed
“Nanoscience Nanotechnology”, and documents were gathered. graph option, select the JCR Journal Map and select the Z-score method
to perform the journal double graph overlap analysis.
2.2. Eligibility criteria The literature search and inclusion screening process underwent
rigorous scrutiny, with both BhW and HnH carefully examining each
The inclusion criteria for the database were restricted to studies that step. To ensure the accuracy and reliability of the software analysis,
satisfied the following conditions: 1) they were written in English, 2) the BhW conducted the primary analysis, while ZcZ served as an indepen­
document type was a review or review article, 3) they were published dent reviewer. Their role was to assess the methodology’s soundness and
before 1 January 2024, and 4) they were affiliated with the research validate the findings to provide a comprehensive and robust assessment
content. Relevant studies that met the specified criteria were included in of the research.
the analysis, whereas those failing to meet these criteria were excluded.
We excluded 7 documents derived from early access, book chapters, 3. Results
editorial material and retracted publications, as well as 49 documents
that were not related to the research topic. Finally, 396 document re­ 3.1. Article distribution by publication year
cords were extracted, each with the following information: abstract,
title, authors, keywords, country/region, institution, journal, and We observed a significant increase in the number of published
reference (Fig. 1).

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B. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116803

studies on exosomes in drug delivery research since 2013, with an Table 1

annual growth rate of 55.18% (Fig. 2A). This trend indicates that the Top 10 countries/regions and 10 institutions.
application of exosomes for drug delivery is receiving increasing Rank Countries/ Count H- Institutions Count H-
attention. regions index index

1 China 221 55 Chinese 29 22

3.2. Countries/regions, Institutions Academy of
Sciences
2 United 88 41 Huazhong 17 12
The publications encompassed 2476 authors hailing from 717 in­ States University of
stitutions across 33 countries. Science
The countries with the highest numbers of publications are listed in Technology
Table 1. China stands is the country with the largest volume of published 3 England 19 16 University of 15 12
Chinese
research papers (count=221,55.80%), followed by the United States
Academy of
(count=88, 22.22%) and England (count=19,4.80%), collectively ac­ Sciences
counting for over half of China’s total publication output. The most 4 Korea 19 13 Shanghai Jiao 15 10
frequently cited country is China (total citations=9788/average cita­ Tong University
tions per article=42.28), followed by the United States (3719/42.26) 5 Italy 15 13 Sichuan 12 8
University
and Korea (1202/63.26) (Fig. 2B). Research published in the Germany 6 India 13 8 University of 11 10
was cited the most times per publication, followed by Netherlands, California
Korea, Iran, United Kingdo and China. The observation of a high volume System
of publications yet a comparatively low number of citations in certain 7 Netherlands 12 11 Jinan University 11 6
8 Spain 11 7 Sun Yat Sen 10 7
countries can be attributed to a range of factors. Among these, the
University
quality of the research itself plays a significant role. Additionally, lan­ 9 Iran 10 7 Zhejiang 10 5
guage barriers can impede the accessibility and comprehension of University
research by international scholars, thereby limiting the potential for 10 Germany 9 7 Harvard 9 6
citations. Furthermore, it is important to note that newly published University

literature often takes time to accumulate citations as it gains exposure

and recognition in the academic community. The H-index is a compre­ nurtures scholarly endeavors and facilitates the dissemination of
hensive indicator that incorporates multiple factors to assess academic knowledge across international boundaries, ultimately enhancing the
accomplishments [25]. The H-index of China has reached the peak level global academic landscape.
of 55, surpassing that of the United States, which stands at 41. This
achievement signifies the significant growth and influence of China’s
research output and scientific impact in recent years. 3.3. Journals
The inclusion of predominantly Chinese institutions in the top ten
summarized in Table 1 indicates a heightened focus among Chinese A total of 41 scientific journals have published research on the
scientists on the field of exosomal drug delivery. The Chinese Academy application of exosomes in drug delivery.
of Sciences (29 publication) has emerged as the leading contributor in Table 2 shows core journals in exosomes’ applications in drug de­
the field of exosomal drug delivery, followed by Huazhong University of livery according to the number of publications. The most relevant
Science Technology (17), University of Chinese Academy of Sciences journal was International Journal of Nanomedicine (52publications/
(15) and Shanghai Jiao Tong University (15). Fig. 3 shows the organi­ 2192citations), followed by Journal of Nanobiotechnology (52/1361)
zation’s collaboration network. The size of the label corresponds to the and ACS Nano (33/3437). The citation relationship between scientific
number of documents, while the thickness of the line reflects the degree and technological journals serves as a manifestation of knowledge ex­
of fit. The Chinese Academy of Sciences and the University of Chinese change, with the cited research representing the forefront of knowledge
Academy of Sciences maintain the closest collaboration. and the reference research forming its foundational basis [26]. The
The proliferation of published articles serves as a vibrant indicator of dual-map overlap method, developed by Chaomei Chen and Loet Ley­
academic exchange, fostering a robust network of collaboration and desdorff, facilitates the assessment, comparison, and differentiation of
cooperation among diverse countries and institutions. This, in turn, publication portfolio features [27]. The purpose of its usage was to

Fig. 2. Publication and citations of articles (A) Trends in the number of publications from 2013 to 2023; (B) Top 10 countries with the highest number of publications
and their number of citations.

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Fig. 3. Institutional cooperation/contributions to publications.

denote the citation links established among academic journals (Fig. 4).
Table 2
In the diagram, the left side represents the citing journal, while the right
Top ten journals and their citation.
side represents the cited journal. The connection between them is
Rank Journal Output JCR IF Citations H- visually depicted by colored lines in the middle. Analysis shows that, in
index
the journal molecular biology/genetics articles usually quoted from
1 International Journal of 52 Q2 8.0 2475 23 physical/material/chemical related journal articles.
Nanomedicine
2 Journal of 52 Q1 10.2 1615 20
Nanobiotechnology 3.4. References
3 ACS Nano 33 Q1 17.1 3746 24
4 Advanced Healthcare 23 Q1 10.0 640 12
Materials A total of 23,604 references were identified in the included studies,
5 Nanoscale 23 Q3 6.7 1307 16 with Fig. 5 presenting the top ten cited references across these studies.
6 Advanced Science 21 Q1 15.1 1199 14 Delivery of siRNA to the mouse brain by systemic injection of targeted
7 ACS Applied Materials & 18 Q2 9.5 1018 14
exosomes was the most frequently cited reference [3]. This study ex­
Interfaces
8 Advanced Materials 18 Q1 29.4 1663 13 amines the utilisation of targeted exosomes for systemic
9 Nanomedicine 17 Q4 5.5 668 12 injection-mediated siRNA delivery to the murine brain. Furthermore,
10 Nanomaterials 15 Q3 5.3 330 10 the therapeutic efficacy of exosome-based siRNA delivery was demon­
strated in mice with a normal genetic makeup, resulting in a significant

Fig. 4. Dual-map overlap.

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Table 3
Exosome-carrying drugs in clinical practice.
Research exosome source document

Cancer breast cancer Exosomes loaded with lapatinib significantly reduced the proliferation of SKBR3 cells, epithelial mammary [54]
thereby increasing the efficacy of the drug’s efficacy. cell
Modification of exosomes from macrophages to enhance their ability to target tumors. macrophage [55]
The biomimetic delivery vehicle of EXO-GO-CO-γ-PGA-MIT can specifically target breast breast cancer cell [56]
tumor cells.
The ability of exosomes loaded with paclitaxel to fight breast cancer. MSC [57]
Exploring the feasibility of using altered exosomes obtained from transgenic DPSCs as dental pulp [58]
vectors to deliver miR-34a mesenchymal stem cell
Potential clinical use of exosomes derived from breast cancer cells in the treatment of breast breast cancer cell [59]
cancer.
gastric cancer The potential efficacy of treating exosomal RPS3 protein in cisplatin-resistant gastric cancer gastric cancer cell [60]
cells could be a promising approach to overcome cisplatin resistance in gastric cancer.
Exosomal delivery of miR-155–5p extracted from paclitaxel-resistant gastric cancer cell lines gastric cancer cell [61]
may be an effective strategy to overcome paclitaxel resistance in gastric cancer.
colorectal Carboxy-terminal MUC1 aptamer-modified exosome-secreted mesenchymal stem cells MSC [62]
cancer encapsulating adriamycin are superior to free doxorubicin in the treatment of colorectal
cancer.
Recent applications of homomimetic nanocarriers in the treatment of colorectal cancer. colorectal cancer cell [63]
The potential of lactogenic exosomes to address intestinal diseases. milk [64]
Plant-derived exosome-like nanoparticles serve as nanocarriers for direct delivery of plant [65]
CRISPR/Cas9-based therapies that specifically target colon cancer cells.
Engineered exosomes loaded with both miR-21i and 5-FU effectively reversed the resistance colorectal cancer cell [66]
of 5-FU-resistant colorectal cancer cells and significantly enhanced cytotoxicity.
bladder cancer Macrophage-derived exosomes administered a combination inhibitor targeting programmed macrophage [67]
cell death ligand 1 and CD73.
Gemcitabine with a delivery system consisting of exosomes derived from M1 macrophages macrophage [68]
enhances cytotoxic effects and triggers inflammatory damage in bladder cancer cells.
The potential of mesenchymal stem cells derived from adipose tissue as a valuable source of AMSC [69]
therapeutic exosomes.
ovarian cancer The viability of utilizing exosomes as a vehicle for delivering the highly effective macrophage [70]
chemotherapy drug cisplatin.
Efficacy of cisplatin exosomes derived from M1 macrophages from umbilical cord blood in macrophage [71]
treating ovarian cancer and overcoming platinum resistance.
lung cancer miRNA-231-Exo extracted from breast cancer cells effectively inhibited the proliferation and breast cancer cell [72]
migration of A549 lung cancer cells.
Exosomes loaded with paclitaxel utilize a carrier consisting of aminoethylbenzamide- macrophage [73]
polyethylene glycol and exhibit significant loading capacity and cancer cell accumulation.
Loading of iRGD-modified lact-derived exosomes with paclitaxel in tumor therapy. milk [74]
Effects of exosomes derived from lung tumors on the tumor microenvironment, metastasis, lung tumor cell [75]
and role in anti-targeting therapy.
Pretreatment with exosomes derived from 4T1 cells from metastatic breast cancer breast cancer cell [76]
circumvents phagocytosis by Kupffer cells and thus improves the efficacy of the delivery
vehicle against tumor metastasis.
brain cancer Investigating whether exosomes derived from brain endothelial cells have the potential to brain endothelial cell [77]
transport anticancer drugs across the blood-brain barrier.
MSC-Exos have the potential to revolutionize the treatment of a wide range of diseases. MSC [78]
Exosomes extracted from glioblastoma and loaded with Semitinib have targeted antitumor glioblastoma cell [79]
properties against U87MG cells.
Effect of exosomes derived from natural killer cells on aggressive glioblastoma. natural killer cell [80]
Bone tissue Bmp2mRNA exosome-enriched hydrogel promotes bone regeneration. HEK 293 T cell [81]
regeneration
Exosomes as carriers for the transport of Icariin improve the ability to promote bone fetal bovine serum [82]
regeneration.
Exosomes were isolated from plasma and loaded with miR-140 to promote differentiation of plasma [83]
bone marrow mesenchymal stem cells into chondrocytes.
This study shows that exosomes rich in miR-375 enhance the ability of bone regeneration in AMSC [84]
rat skull defect models.
Neurodegenerative Alzheimer’s Targeting APP-expressing neuronal cells to ameliorate cognitive decline in AD mice using hippocampus neuron [85]
disease disease Fe65-designed neuronal exosomes encapsulating vincristine-B. cell
This study uses adipose stem cell-derived exosomes as carriers to enhance the therapeutic AMSC [86]
effect of coenzyme Q10 on AD.
Exosomal delivery of Tom40 across the blood-brain barrier protects cells from hydrogen HEK293 cell [87]
peroxide-induced oxidative stress.
This study developed quercetin-loaded plasma exosomes to enhance brain targeting, plasma [88]
significantly improving the bioavailability of quercetin.
This article studied the therapeutic potential of exosomes loaded with miR-29 in AD. HEK-293 T cell [89]
Curcumin-loaded exosomes achieve efficient blood-brain barrier crossing through receptor- macrophage cell [90]
mediated endocytosis and have great potential for improving drug-targeted delivery and
neuronal function recovery in AD therapy.
Parkinson’s This study developed a self- oriented nanocarrier based on exosomes, which significantly MSC [91]
disease improved the movement and coordination ability of PD model mice.
Exosomes loaded with catalase showed significant neuroprotective effects in both in vivo macrophage cell [92]
and in vitro models of Parkinson’s disease.
Therapeutic potential of RVG- exosome-delivered shRNA-MCs in the treatment of murine dendritic cell [93]
Parkinson’s disease.

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Fig. 5. The number of citations of highly cited references in this filed and the top ten articles from 2013 to 2023.

reduction (60% mRNA and 62% protein) in the expression of a crucial nanoparticles”, cluster#6 “biomimetics” and cluster#7 “regenerative
target for Alzheimer’s disease treatment, BACE1. medicine”.
The knowledge base was revealed by employing a reference co-
citation network analysis technique (Fig. 6). Clusters were identified
through the selection of the top 6.0% of articles for each year as a 3.5. Keywords
distinct segment. After the completion of the clustering process, both the
modularity Q score and weighted mean silhouette S surpassed 0.5, 3.5.1. Research direction
attaining values of 0.6366 and 0.8512 respectively. The aforementioned By conducting keyword analysis, it is possible to effectively sum­
factors indicate that the network was effectively partitioned into clus­ marise individual research subjects and explore the emerging areas and
ters, exhibiting minimal inter-cluster connectivity and desirable uni­ future prospects within this specific field of study. In order to enhance
formity within each cluster. The study employed index terms derived the identification of primary research areas in the field of drug delivery
from literature as clustering indicators. The largest clusters were clus­ using exosomes, a comprehensive analysis was conducted on terms
ter#0 “dual targeting”, cluster#1 “cancer immunotherapy”, cluster#2 encompassing title, abstract, and author keywords utilising CiteSpace.
“iron oxide nanoparticles”, cluster#3 “blood-brain barrier”, cluster#4 The Modularity Q score of 0.6832 indicated a moderate division of the
“therapeutic drug monitoring”, cluster#5 “plant-derive vesicles-like network into loosely connected clusters, which exceeded the threshold
value of 0.5. The Weighted mean silhouette score of 0.8487 also

Fig. 6. Reference co-citation clustering map.

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B. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116803

exceeded the critical level of 0.5, suggesting that satisfactory cluster these vesicles for targeted delivery of anti-inflammatory agents and
homogeneity levels had been attained. The largest cluster #0 was “drug elucidated the underlying mechanisms involved in their clinical appli­
delivery”, cluster #1 “cancer immunotherapy”, cluster #2 “mesen­ cations. This research provides valuable insights into the role of
chymal stem cells”, cluster #3 “targeting ligands”, cluster #4 “surface MSC-Exos in inflammatory diseases [32]. Naseri et al. conducted both in
modification”, and cluster #5 “macrophage”. The emergence of cluster vitro and in vivo experiments, demonstrating the effective infiltration of
#0 “drug delivery” was observed as the initial cluster in the temporal tumor sites by MSC-Exos. They further established that these exosomes
analysis of term evolution (Fig. 7), and clusters #1 to #4 sustained a served as an optimal nanocore for targeted delivery of inhibitory oli­
significant level of intensity from 2018 to 2021 almost simultaneously. gonucleotides to tumor tissues, resulting in a significant reduction in the
This indicates that the investigation into the utilisation of exosomes expression levels of miR-142–3p and miR-15. This study highlights the
released by genetically modified MSCs in cancer therapy has attracted potential of MSC-Exos in tumor therapy [33].
significant attention from 2018 to 2021. #2 “cancer immunotherapy”, immunotherapy is a powerful treat­
#0 “drug delivery”, in the realm of drug delivery, the quest for ment modality that harnesses the host’s immune system to counter tu­
advanced methods that can enhance the treatment of intractable human mors that have evaded immune surveillance and induced
diseases has led to significant research. Exosomes, owing to their immunological tolerance. Recent studies have shown that exosomes
favorable biocompatibility, stability in circulation, minimal toxicity, may significantly enhance the efficacy of immunotherapy by improving
and targeting capabilities, have emerged as a promising candidate for the delivery, biological distribution, and release kinetics of immunosti­
targeted delivery of therapeutic agents to specific cells and tissues. In a mulatory small molecules and biological agents in target tissues. Zhao
groundbreaking study by Nordmeier et al., exosomes were utilized to et al. demonstrated the potential of exosomes secreted by M1 macro­
deliver therapeutic nucleic acids, overcoming the significant challenges phages encapsulating docetaxel to induce M1 macrophage activation
of low delivery efficiency and rapid clearance by the immune system. within the immune microenvironment of breast cancer. This activation
This approach holds immense potential in enhancing the efficacy of led to a significant suppression of tumor growth, highlighting the role of
nucleic acid-based therapies [28]. Li et al. took this concept further by exosomes in targeting and activating specific immune cells within the
employing doxorubicin-loaded exosomes to treat colorectal cancer. In tumor microenvironment [34]. Li et al. took a different approach by
vivo experiments revealed a significant reduction in cardiotoxicity genetically modifying a mouse T cell line to enhance the expression of
compared to traditional administration methods, demonstrating the PD-1. The resulting extracellular vesicles were able to augment the
therapeutic potential of exosome-based drug delivery in cancer treat­ functionality and proliferation of CD8+ effector T cells, thus facilitating
ment [29]. More recently, Wan et al. modified exosomes surface proteins the immune eradication of malignant cells. This study underscores the
of exosomes, resulting in a drug delivery system with enhanced circu­ potential of genetically modified exosomes in boosting the immune
latory stability and reduced toxicity. This advancement not only im­ response against cancer [35]. The team led by Shen has developed a
proves the biocompatibility of exosomes but also extends their nanoraspberry coated with exosomes (RB@Exo) that exhibits remark­
application in various therapeutic areas [30]. able immunomodulatory properties. This nanoconstruct is able to
#1 “mesenchymal stem cells”, MSC-Exos the ability to mimic the establish immune tolerance in lung metastases while facilitating T cell
functions of MSCs while overcoming their clinical limitations (Fig. 8). activation. This dual action holds promise in the treatment of metastatic
Furthermore, these exosomes offer significant advantages, including the cancer, where both immune suppression and immune activation are
absence of immunogenicity and tumor risk. Due to these unique prop­ crucial for successful treatment [36].
erties, MSC-Exos have garnered extensive attention for their applica­ #3 “targeting ligands”, the exosomal membrane is characterized by a
tions in various therapeutic areas, including tissue damage repair and high density of receptors or ligands, which enables them to engage in
regeneration, anti-inflammatory and immune regulation, drug delivery, specific interactions with target cells. This selective recognition capa­
and tumor therapy. This approach is considered a novel cell-free ther­ bility allows exosomes to precisely localize and target specific cells,
apeutic strategy. Zou et al. proposed that MSC-Exos could promote tissues, or organs. The targeting efficacy of exosomes can be further
tendine-bone healing through anti-inflammatory, angiogenesis, osteo­ enhanced through modifications to the ligands present on their mem­
genesis and inhibiting bone lysis [31]. This finding offers a promising brane. Gong et al. modified milk-derived exosomes with the CD44-
therapeutic option for the treatment of tendinopathy and related bone specific ligand hyaluronic acid (HA) to obtain nanocarriers (HA-mExo-
injuries. Wang et al. investigated the therapeutic potential of MSCs and FA) that can be targeted and delivered to hepatocytes [37]. Additionally,
their extracellular vesicles(MSC-Exos) in the management of exosomes derived from LIM1215 cells expressing A33 were isolated and
inflammation-related disorders. Their study explored the capacity of conjugated with A33 antibodies, resulting in a complex that exhibited

Fig. 7. Keywords clustering temporal evolution.

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Fig. 8. Application of mesenchymal stem cell-derived exosomes.

efficient targeting towards colon cancer cells expressing A33 [29]. Liu efficiently deliver siRNA and Panobinostat to treat diffuse intrinsic
et al. utilized cyclic RGD peptide to modify extracellular vesicles derived pontine glioma with PPM1D mutation [43]. Similarly, Zhao et al. uti­
from MSCs for therapeutic intervention in retinal degeneration, lized exosomes derived from M1 macrophages to encapsulate docetaxel,
demonstrating superior targeting capabilities compared to traditional targeting breast cance. The combination of M1 macrophage-derived
methods [38]. exosomes and docetaxel leverages the targeting potential of the exo­
#4 “surface modification”, Surface modification of exosomes holds somes to enhance the therapeutic efficacy of the anticancer drug in
immense potential for modulating their functionality by altering their breast cancer treatment [34].
surface molecular composition. Such modifications can lead to en­
hancements in targeting efficiency, improved stability, acquisition of 3.5.2. Research frontiers and hotspots
therapeutic capabilities, and various other benefits. To illustrate, Guo Burst keywords, serving as indicators for potential areas of height­
et al. employed monoclonal antibodies targeting GAP43 to conjugate ened activity and emerging patterns, primarily function to detect sudden
bioengineered neurons with exosomes, aiming to facilitate the precise shifts in data [44]. As illustrated in Fig. 9, keywords exhibiting a sudden
transportation of ischemic neurons characterized by upregulated GAP43 surge in usage in these publications were identified utilising Citespace’s
expression. This approach enables the targeting of exosomes specifically burst detection feature. Two principal areas of current research interest
to ischemic neurons, potentially enhancing therapeutic outcomes [39]. were identified: cell-derived exosomes (2021–2023) and the blood-brain
Zhai et al. modified human umbilical cord-derived MSCs with CD73 and barrier (2021–2023). It is postulated that these terms represent nascent
isolated extracellular vesicles with high expression of CD73. The CD73 frontiers in drug delivery research related to exosome applications.
on the surface of EVs has the ability to reduce the concentration of ATP, The paper discusses the potential of using cell-derived exosomes as a
increase the level of adenosine, and reduce spinal cord inflammation. novel drug delivery vehicle, emphasizing the importance of considering
This modification endows the EVs with anti-inflammatory properties, the characteristics of the donor cells to enhance the efficacy of exosome-
which may be beneficial in the treatment of spinal cord injuries or other based therapies. Exosomes are released into the extracellular matrix
inflammatory conditions [40]. Wu et al. have developed after being formed from multivesicular vesicles within cells, and they
angiopep-2-modified exosome-mimetics that exhibit enhanced carry the same inclusions (biomolecules like proteins, lipids, and nucleic
blood-brain barrier penetration capabilities. This modification allows acids) as the donor cell. This allows exosomes to perform some of the
the exosome-mimetics to traverse the blood-brain barrier, opening up biological functions of the donor cell [45]. Immune cell-derived exo­
possibilities for the treatment of brain-related diseases. The multi­ somes, such as those from macrophages and NK cells, have significant
functionality of these modified exosome-mimetics suggests their po­ roles in modulating immune responses and fighting viruses and tumors.
tential as a versatile platform for targeted drug delivery to the central In a study conducted by Hashemi et al., the therapeutic effects of sor­
nervous system [41]. afenib were compared when administered with and without encapsu­
#5 “macrophages”, macrophages play a pivotal role in regulating the lation within exosomes derived from NK cells on breast cancer
immune microenvironment surrounding tumors. Specifically, M1 mac­ spheroids. The findings revealed that exosomes encapsulating sorafenib
rophages exhibit a tumor-targeting ability and phagocytic function to­ exhibited superior anti-cancer effects compared to SFB therapy alone
wards cancer cells, which is attributed to their unique surface proteins. [46]. Similarly, Zhu et al. previously demonstrated the promising po­
Consequently, exosomes derived from M1 macrophages can inherit this tential of exosomes derived from chimeric antigen receptor T-cells,
targeting effect and serve as effective carriers for delivering a wide range armed with a tumor-targeting moiety and cytotoxic components(gran­
of anticancer drugs. Kim et al. isolated exosomes from macrophage zyme B and perforin), as delivery vehicles for paclitaxel in cancer
culture supernatants and conjugated them with aminoethylanisamide- therapy. These specialized exosomes showed remarkable potential in
polyethylene glycol. Subsequently, paclitaxel was loaded into these targeting and destroying cancer cells [47]. Furthermore, Kim and col­
modified exosomes as a therapeutic agent to target lung carcinom. This leagues developed a nanoparticle system that harnesses exosomes
approach harnesses the targeting capabilities of M1 macrophage- derived from macrophages to enhance the efficacy of targeted chemo­
derived exosomes to deliver paclitaxel specifically to lung cancer cells therapy in triple-negative breast cancer. Their results indicated signifi­
[42]. Shan et al. designed a biomimetic nano-drug delivery system uti­ cant improvements in both the cellular uptake efficiency and antitumor
lizing exosomes derived from macrophages. This system efficiently de­ potency of doxorubicin when delivered via this exosome-based nano­
livers siRNA and Panobinostat to treat diffuse intrinsic pontine glioma particle system [48].
with PPM1D mutationwith exosomes from macrophages, which can Tumor cell-derived exosomes possess an innate ability to

8
B. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116803

Fig. 9. Top 8 keywords with strongest citations bursts.

preferentially deliver their cargo to tumor cells due to homotypic in­ 4. Discussion
teractions. This phenomenon has been harnessed for targeted drug de­
livery applications in anti-cancer therapy. Several studies have 4.1. General information
demonstrated the potential of this approach. Qiao et al. injected HT1080
or HeLa exosomes into nude mice bearing subcutaneous HT1080 tumors The present study involved the analysis of a total of 396 scientific
and observed that HT1080-derived exosomes showed a tendency to papers that focused on the utilisation of exosomes for drug delivery.
accumulate specifically at the HT1080 tumor site [49]. Saari et al. These selected papers were published between 2013 and 2023. The
further explored this concept by loading paclitaxel onto exosomes number of published works in China accounted for the highest propor­
derived from autologous prostate cancer cells. They found that this tion, reaching 55.80% of all publications, while the United States closely
approach increased the cytotoxicity of paclitaxel, likely due to its more followed with a percentage of 22.22%. The Chinese Academy of Sciences
efficient delivery to prostate cancer cells via the tumor-derived exo­ has emerged as a leader in terms of the number of its publications. The
somes [50]. Chen et al. also utilized the targeting ability of breast cancer International Journal of Nanomedicine has demonstrated exceptional
cell-derived exosomes and successfully increased the local drug con­ productivity in terms of article publication. Cell-derived exosomes and
centration in breast tumors. This approach capitalized on the homotypic blood-brain barrier are considered to be the current research hotspots.
interactions between breast cancer cell-derived exosomes and breast
cancer cells, leading to enhanced drug delivery and potentially
4.2. Advantages and challenges
improved therapeutic outcomes [51].
The burgeoning keyword "blood-brain barrier" has garnered signifi­
Exosomes have garnered significant interest owing to their unique
cant attention in the medical community, particularly with the emer­
properties and inherent ability to transport macromolecules. The
gence of exosomes as a promising area of research. Their remarkable
exploration of exosome-based drug delivery systems is gaining promi­
biocompatibility, stability, and capability to traverse the blood-brain
nence in research. However, challenges pertaining to the extraction,
barrier have sparked extensive utilization in the treatment of diverse
isolation, drug delivery efficiency, targeting, and in vivo circulation time
brain disorders, encompassing degenerative diseases of the central
of exosomes remain obstacles to their clinical translation. Future
nervous system, brain tumors, and cerebrovascular conditions.
research is anticipated to primarily address these concerns.
In a recent study, Shan et al. innovated a targeted drug delivery
In the realm of exosome extraction and isolation, it is noteworthy to
system, leveraging modified macrophage exosomes for the treatment of
emphasize that a wide array of cell types inherently possess the capacity
diffuse endogenous pontoglioma harboring protein phosphatase 1 mu­
to produce exosomes. However, it is imperative to acknowledge that not
tations. This system incorporates panobinostat and PPM1D-siRNA, of­
all exosomes generated by cells are suitable candidates for drug delivery
fering a precision approach to treating this complex malignancy [43].
applications. This assessment is grounded in considerations such as their
Additionally, Wang et al. demonstrated the potential of
production efficiency and the specific types of surface proteins they
curcumin-treated exosomes in traversing the blood-brain barrier and
harbor. Presently, therapeutic exosomes are predominantly sourced
effectively penetrating brain tissue via receptor-mediated transcellular
from MSCs and immune cells. Consequently, the quest for novel and
transport, presenting promising avenues for the treatment of Alz­
efficient methods to isolate exosomes, with a particular focus on maxi­
heimer’s disease [52]. Furthering this research, Zhou et al. have devel­
mizing their therapeutic potential, holds paramount importance.
oped Exo@TDPs, exosomes derived from glioblastoma cells that carry
To bolster the efficiency of drug therapy, researchers have devised
chemotherapy agents temozolomide and doxorubicin. Through rigorous
various strategies for integrating drugs into exosomes, encompassing
in vitro and in vivo experiments, they have successfully demonstrated
both pre-loading and post-loading techniques. Pre-loading methods,
the ability of Exo@TDPs to traverse the blood-brain barrier, selectively
including transfection and co-incubation, involve loading the drug into
target glioblastoma cells, and penetrate deeply into the tumor paren­
the donor cell prior to the separation of exosomes. This approach en­
chyma, thereby enhancing therapeutic efficacy [53].
sures that the drug is encapsulated within the exosome during its natural
biogenesis. A key advantage of this technique is that it facilitates the
loading of high molecular weight drugs without compromising the
integrity of the exosome membrane. On the other hand, the recharging

9
B. Wei et al. Biomedicine & Pharmacotherapy 176 (2024) 116803

technique directly incorporates medications into pre-isolated exosomes by delving into the current research trajectory and envisioned future
through methods such as incubation, electroporation, ultrasound treat­ trajectory of exosomes as drug delivery systems, employing bibliometric
ment, extrusion, and freeze-thaw cycles. The drug loading capacity and techniques. As of now, studies pertaining to exosomes in drug delivery
efficiency vary across these different methodologies. Nevertheless, systems have been predominantly centered around nanoparticles, drug
compared to the highly efficient industrial production of artificial li­ delivery modalities, extracellular vesicles, biodistribution, and cancer
posomes, exosomes exhibit considerably lower drug loading efficiency. therapy. It is anticipated that future advancements will be steered to­
To enhance the efficacy of exosome-mediated drug delivery, the key lies wards advancements in exosome preparation and isolation methods,
in developing an optimized strategy tailored to the specific character­ optimization of drug loading efficiency, targeting capabilities, and
istics and drug transport capabilities of exosomes. This approach will prolongation of circulation time in vivo.It is pertinent to mention that
likely involve a combination of techniques, including the refinement of our research holds certain limitations, one of which is the primary focus
pre-loading methods to maximize drug encapsulation efficiency and the on nanomaterials, without integrating a pharmacological perspective
exploration of novel post-loading techniques that preserve exosome for further refinement and augmentation.
integrity while improving drug loading capacity.
In natural cells, the lipid composition of exosomes varies according Publisher’s note
to their doner cells. In addition to some specific proteins associated with
biogenesis, such as CD9, CD81, and CD63, various receptors and adhe­ The opinions expressed in this article belong solely to the authors
sion molecules are present on the surface, which may be related to its and do not necessarily reflect the views of their affiliated organizations,
targeting ability. Therefore, some researchers tried to modify the doner or those of the publisher, editors, and reviewers. The publisher does not
cells through genetic engineering and design exosomes with specific guarantee or endorse any product that may be mentioned or evaluated
ligands to enhance their targeting. For example, Wang et al. transfected in this article, nor does it validate any claims made by its manufacturer.
the lentiviral vector containing iRGD peptide gene into HEK-293 T cells
to obtain new exosomes [94]. Some researchers also coated the exocrine Funding
surface with nano-magnetic materials to improve the targeting ability
[95]. This work was supported by the key project of the National Natural
Moreover, extensive research has elucidated that exosomes origi­ Science Foundation (82030091), the key project of the LiaoNing Science
nating from cancer cells exhibit a remarkable ability to precisely target Foundation (2023JYTMS 20230135, 2022JH6/100100037, 2022JH2/
their parental cells. Nevertheless, owing to their inherent carcinogenic 20200034, 2022JH1/10400001, 2021JH2/10300023).
implications, these exosomes are predominantly utilized as diagnostic
biomarkers for cancer, rather than as vectors for drug delivery. Over­ CRediT authorship contribution statement
coming this limitation holds immense promise for introducing a novel
paradigm in personalized and precision cancer therapy. Furthermore, Bohua Wei: Writing – original draft, Software, Methodology,
researchers have discovered that proteins situated on the surface of Conceptualization. Qian Cao: Writing – review & editing, Supervision,
exosomes can significantly enhance their half-life within the circulatory Conceptualization. Haonan Huang: Writing – original draft, Formal
system. For instance, CD47 has been shown to prolong exosome stability analysis, Conceptualization. Zhichang Zhang: Writing – review &
by restricting their clearance by mononuclear phagocytes. Therefore, editing, Supervision, Software, Data curation, Conceptualization.
strategic modifications to the surface of exosomes could potentially Xiaoyu Song: Writing – review & editing, Funding acquisition,
extend the duration of therapeutic effects and mitigate the need for Conceptualization.
frequent administrations.
Exosome drug-carrying technology, a frontier in biomedical
Declaration of Competing Interest
research, is revolutionizing our approaches to disease treatment. This
technology, when integrated with established clinical modalities, yields
The authors declare that they have no known competing financial
remarkable therapeutic synergies. In the realm of tumor therapy, for
interests or personal relationships that could have appeared to influence
instance, exosome-mediated drug delivery can precisely target chemo­
the work reported in this paper.
therapeutic agents or radiotherapy sensitizers to tumor tissues, thereby
elevating drug concentrations and efficacy within the tumor mass while
Data availability statement
minimizing the deleterious side effects on healthy tissues. Furthermore,
exosomes have the potential to serve as tumor vaccine antigens and
The data that support the findings of this study are available from the
enhancers, enhancing immunotherapy’s ability to activate the patient’s
corresponding author upon reasonable request.
immune system and facilitate the specific elimination of tumor cells. In
the domains of gene therapy and cell therapy, the encapsulation of
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