In collaboration with National Natural Science Foundation of China and National Science Library at the Chinese Academy of Sciences, this detailed landscape of synthetic organic chemistry was published jointly in Organic Letters and the Journal of Organic Chemistry. This publication reviews hidden connections and new opportunities from within the CAS Content Collection. Three important research areas were chosen: enzyme catalysis, photocatalysis, and green chemistry. This will help researchers and decision-makers understand the current state of the worldwide research effort in this area and help them foresee potential prospects and applications for organic synthesis in the future.

Despite being a well-established discipline, synthetic organic chemistry has continued to advance in the last decade with the goal of meeting society's needs in all parts of life. It is important to understand the history of organic synthesis because of its significance for chemistry, technology, and even humanity.

In collaboration with National Natural Science Foundation of China and National Science Library at the Chinese Academy of Sciences, this detailed landscape of synthetic organic chemistry reveals hidden connections and new opportunities from within the CAS Content Collection. From publication trend analysis and subject matter experts' reviews, three important rising organic synthesis research areas were chosen: enzyme catalysis, photocatalysis, and green chemistry. This report will help researchers and decision-makers understand the current state of the worldwide research effort in this area and help them foresee potential prospects and applications for organic synthesis in the future.

Exosomes are a nanosized subset of extracellular vesicles released from cells as part of their normal physiology or under certain pathologies that are enclosed by a lipid bilayer membrane. First discovered as “platelet dust” in human plasma, they have since been shown to be secreted by most eukaryotic cells, participating in a wide range of physiological and pathological processes.

In previous blogs, we uncovered an overview of the exosome landscape and introduced the ways in which exosomes can potentially be utilized in drug delivery and diagnostics. For the final part of our three-part blog series, we will highlight the breadth of exosome research that is underway in these areas, examining the key developments and future perspectives in this dynamic area.

The key players in therapeutic exosome research

The number of companies that are utilizing exosomes for therapy is rapidly expanding, with both pre-clinical and clinical companies progressing exosome therapeutics through their pipelines. Using data from the CAS Content Collection™, the largest human-curated collection of published scientific knowledge, we explored the targeted diseases that these therapeutic companies are focusing on. We found that the most highly represented targeted diseases in exosome research are cancer, neurological and neurodegenerative diseases, lung diseases, and wound healing, indicating a large amount of candidate exosome products in these areas (Figure 1). While most exosome research platform companies have portfolios that cover multiple therapeutic areas (e.g. VivaZome, Avalon Globocare, and Vitti Labs), some companies tend to specialize in a particular area, such as Kimera Labs and its focus on skin regeneration and wound healing.

An appraisal of companies who are investing in preclinical exosome research shows that the US is leading the way, with a diverse pipeline of therapeutic exosomal products. California-based biotech company Capricor Therapeutics is developing multiple exosome platforms including cardiosphere-derived cell exosomes, engineered exosomes, and an exosome-based vaccine for COVID-19. Though their exosome platform is still in the preclinical stages, they have seen promising data in several indications and partnered with other academic institutions to drive their exosome research forward.

Xollent Biotech is another key player in exosome research, with a diversified pipeline of exosome therapeutics. The versatility of exosomes allows for alternative routes of administration, with pipeline treatments comprising of an intravenous patch for treating myocardial infarction, a spray for alopecia, and a needleless injection to combat skin aging. Other companies focusing on cosmetics include Exocel Bio and Florica Therapeutics, which are exploring regenerative stem cell-derived exosome therapeutics in aesthetics and aging.

Diagnostic exosome research: current progress and future directions

As we explored in the previous blog in the series, exosomes have several properties that make them ideal biomarkers, including durability, specificity, and sensitivity. Consequently, the application of exosomes as biomarkers and in diagnostic testing is a growing area of research interest. Though research is still in its infancy, several companies have conducted preclinical exosome research in this area, particularly in cancer. Notable examples include Mercy Bioanalytics and their Halo test for early cancer detection, and research from the University of Texas MD Anderson Cancer Center investigating the use of glypican-1 positive circulating exosomes for detecting early pancreatic cancer.

Organizations are also optimizing diagnostic assays in other therapeutic areas. For example, a collaboration between Harvard Medical School, USA, and Wenzhou Medical University, China, is employing an incorporated Tear-Exosomes Analysis via Rapid-isolation System (iTEARS), which has shown potential in molecular diagnostics of dry eye disease and diabetic retinopathy. Neurodegenerative diseases are also a key focus in exosomal biomarker studies. Researchers at the University of California, San Francisco Medical Center have discovered a panel of biomarkers that could play a role in diagnosing early-onset Alzheimer’s Disease.

Exosome therapeutics in clinical trials

Currently, the total number of clinical trials registered at https://clinicaltrials.gov for exosomal therapeutics is 59 clinical trials. The most highly researched targeted diseases for exosome therapeutics include lung disease (11 clinical trials), SARS-CoV-2 infections (9 clinical trials), along with cancer, heart disease, and neurological diseases (all with 4 clinical trials). Highlighted clinical trials with respect to these diseases are listed in Table 1. For a more comprehensive list of the therapeutics clinical trials, see our recently published Exosome Insight Report.

Table 1. Highlighted exosome therapeutic clinical trials

Exosome diagnostics in clinical trials

Currently, on https://clinicaltrials.gov there is a total of 208 clinical trials with exosomes being used for diagnosis. Over half of these clinical trials (108 clinical trials) are related to cancer diagnosis utilizing exosomes. Other highly represented diseases include neurological diseases (15 clinical trials), cardiovascular diseases (13 clinical trials), and lung diseases (6 clinical trials). Early diagnosis of these diseases is crucial for a better prognosis. The large number of clinical trials of exosomes in diagnosis highlights the value and advantage of using exosomes in early disease diagnosis. Table 2 highlights the companies, medical centers, and universities related to exosome diagnosis of these diseases. For a more comprehensive list of the diagnostics clinical trials, see our recently published Exosome Insight Report.

Table 2. Highlighted exosome diagnostic clinical trials

Exosomes as the disease target in clinical trials

Using exosomes as targets is another avenue that is being explored for disease treatment. Aetholon Medical is a California-based clinical company that has designed an investigational medical device called the Hemopurifier. Targeting circulating exosomes, the Hemopurifier captures viral, bacterial toxin, and cancer exosomes to treat disease. To date, Aetholon has used the Hemopurifer to treat patients with Ebola, hepatitis C, HIV, and COVID-19. Their two current clinical trials are explored in Table 3.

Table 3. Highlighted clinical trials that target exosomes (physical elimination) for disease treatment

Overcoming outstanding challenges in exosome research

Exosomes are an exciting area of research and present enormous potential for both diagnostic and therapeutic use. However, the clinical applications of exosomes, although highly promising, are currently hindered by gaps in knowledge. Therefore, future work must focus on prioritizing the exact mechanisms of exosome biogenesis and uptake, along with elucidating their interactions with target cells, which together will help researchers advance their therapeutic potential. Another key hurdle to overcome in exosome research is the current challenges with exosome isolation, with a lack of standardization of these processes delaying clinical utility. Finally, the breadth of exosome applications in the pipeline will mean specific regulatory classification and jurisdiction issues need to be clarified to enable development plans to be established.

While significant knowledge gaps must be dealt with, exosome research presents significant opportunities in treating a plethora of diseases – we’ve come a long way from platelet dust.

To learn more, see our recently published Exosome Insight Report.

Exosomes are a nano-sized subset of extracellular vesicles released from cells as part of their normal physiology or under certain pathologies. In our previous blog on exosomal evolution, we discussed the advancement of these natural nanoparticles, from their initial discovery to the recent boom in extracellular vesicle research.

In part two of this three-blog series, we will explore further insights from the CAS Content Collection™, the largest human-curated collection of published scientific knowledge, summarizing the key applications of exosome therapy in drug delivery and diagnostics.

Rising research trends in exosome therapy

Using the CAS Content Collection, we analyzed the presence and trends of certain key concepts in scientific publications relevant to exosome applications in drug delivery and diagnostics (Figure 1). The keywords ‘targeting’ and ‘biomarker’ came out on top, reflecting the growing interest in exosomes in therapeutics. Significantly, analysis of the key concepts during the years 2017–2021 revealed a sharp increase in the term “blood-brain barrier” over the past two years, indicating that this is a hot topic in exosome therapy research. As we learned in part one, exosomes can cross the blood-brain barrier. The ability to cross this highly selective boundary not only makes exosomes valuable diagnostic tools, but it may also provide a means to deliver therapeutic cargo to the brain, helping to treat cancer and traumatic brain injuries.

Figure 1. Key concepts in the scientific publications relevant to the exosome applications in drug delivery and diagnostics: (A) Number of publications exploring key concepts related to exosome applications in therapy and diagnostics. (B) Trends in key concepts presented in the articles related to exosome therapy applications and diagnostics during the years 2017−2021. Percentages are calculated with yearly publication numbers for each key concept, normalized by the total number of publications for the same concept in the same period.

The vital first step in exosome therapy: isolating and purifying exosomes

Before exosomes can be utilized in large-scale medical practice, it is crucial that these nano-sized particles are precisely distinguished from a wide spectrum of cellular debris and interfering components. There is no single standardized approach to exosome separation and analysis, with each approach providing unique strengths and limitations (summarized in Table 1). While ultracentrifugation was once considered the gold standard approach, in recent years precipitation and microfluidic methods have proved more popular due to their ability to purify exosomes without causing potential damage (Figure 2). A combination of several of these methods has been suggested as a promising strategy for the improvement of the isolation outcome. This is to provide exosome subsets with high purity with respect to size, morphology, concentration, the presence of exosome-enriched markers, and the lack of contaminants.

Table 1. Major methods of exosome isolation/purification

Figure 2. Trends in the number of documents related to exosome therapy applications and diagnostics concerning various exosome isolation methods during the years 2014−2021. (Percentages are calculated with yearly publication numbers for each isolation method, normalized by the total number of publications for the same isolation method in the same period.)

Exosome therapy and drug delivery

Once exosomes have been extracted and purified, how do we then turn them into effective drug delivery systems? Luckily exosomes are made for this role, combining the benefits of both synthetic nanocarriers and cell-mediated drug delivery systems, while avoiding their limitations. The first step to harnessing these properties is ‘cargo loading’, the process of packing exosomes with therapeutic materials. Several cargo loading methods have been employed for this purpose, each with their own advantages and disadvantages (Table 2).

Table 2. Cargo loading techniques

As a form of cell-to-cell messengers, exosomes play a crucial role in different physiological processes. As such, exosomes secreted by different tissues and cells exhibit unique properties. For example, tumor-derived exosomes have been found to impact tumor properties such as growth, angiogenesis, invasion, and metastasis. In contrast, exosomes from mesenchymal stem cells (MSCs) have properties that make them ideal for use as adjuvants to support and complement other therapeutic modalities. In fact, a US-based company, Direct Biologics, is exploring the utility of the MSC-derived therapeutic ExoFlo in clinical trials for ulcerative colitis, solid organ rejection, and COVID-19, to name a few.

Though the potential applications of exosome therapy are wide-ranging, by far the most common area of exosomal research is cancer, followed by inflammation and infection. By analyzing the correlation between exosome donor cells and the diseases they have been applied to, a clear pattern emerges. Antigen-presenting cells and natural killer cells are most frequently used in cancer studies. Macrophages and stem cells are the most frequently used in inflammation, while antigen-presenting cells and T-cells are frequently used in infection (Figure 3).

Figure 3. Correlation between exosome donor cells and the diseases to which the exosomes have been applied to in the studies related to exosome therapy and diagnostics, as represented by the number of documents in the CAS Content Collection.

The varied targeted applications of exosome therapy

Another rapidly expanding and noteworthy application of exosomes is their use as therapeutic agents. Exosome systems have been applied as therapeutic or diagnostic tools to a wide range of disorders. Our analysis of the CAS Content Collection shows that most publications (68%) on exosome therapy are associated with cancer. Exosomal microRNAs (miRNAs) have been shown to inhibit cancer cell proliferation, migration, and invasion. This approach has been explored in various malignant cell subtypes, including those for bladder, colorectal, and breast cancer. Exosomes also have enormous therapeutic potential in neurodegenerative, inflammatory, and cardiovascular diseases, which are also represented (Figure 4).

Figure 4. Distribution of the publications in the CAS Content Collection related to applications of exosome therapy and diagnostics with respect to the target diseases.

As exosomes are involved in the pathogenesis of diseases such as cancer, a successful therapeutic strategy may involve reducing elevated exosome production and circulation to normal levels to prevent disease progression. Several ongoing studies are exploring the impacts of modulating the exosome therapy pathway at various steps, including its production, release, and uptake. Physical elimination of exosomes has also been explored in cancer cells, with researchers hypothesizing that this elimination can hamper the communication between tumor cells that contribute to tumor progression.

Diagnostic use of exosomes

To be feasible for clinical use, a biomarker must exhibit several properties. It should be easy to access, cost effective, specific, highly sensitive, and measurable. Due to their unique properties, exosomes already tick several of these boxes, showing superiority over conventional serum-based biomarkers, particularly in regard to diagnostic sensitivity and accuracy.

There are several advantages to employing exosomes in this therapeutic way. Firstly, as the pathological status of cells greatly affects the content of exosomes (as observed in Alzheimer’s disease), studying these extracellular vesicles can provide a window into the disease state of the tissue. They are also innately stable, with a lipid bilayer that enables them to withstand degradation even within harsh microenvironments. In terms of practicality, exosomes can be easily and non-invasively isolated from biological fluids such as urine, blood, and even tears. Once extracted, they can be stored by freezing, freeze-drying, or spray-drying. Finally, unlike many conventional serum biomarkers, exosomes can pass through the blood-brain barrier, providing information about brain cells that would be otherwise difficult to obtain. Several candidate exosomal protein biomarkers (Table 3) and nucleic acid biomarkers (Table 4) are currently being explored. For the expanded list of these biomarkers see our ACS publication, Exosomes – Nature’s Lipid Nanoparticles, A Rising Star in Drug Delivery and Diagnostics.

Table 3. Examples of exosomal proteins for clinical diagnostic applications

Table 4. Exosomal miRNAs as cancer therapeutic and diagnostic agents

The interest in exosomes as biomarkers is reflected in the extensive growth in the number of documents related to applications of exosome therapy and diagnostics, as revealed by analysis of the CAS Content Collection (Figure 5). While it appears at first glance that documents related to therapeutics come out on top, the general percentage of documents is equally distributed between both applications.

Figure 5. Diagnostic vs. therapeutic application of exosomes: (A) Comparison of the number of documents related to applications of exosome therapy vs. diagnostics; Inset: Annual growth of the number of documents related to exosome applications in therapy vs. diagnostics. (B) Comparison of the number of documents related to exosome applications in therapy vs. diagnostics with respect to their role indicators (THU, therapeutic; DGN, diagnostic).

While the current exosome therapy research is promising, many studies remain in the preclinical stage. That said, how close are we to utilizing the full potential of exosomes in therapeutics and diagnostics? What are the obstacles and challenges that stand in our way? In our final article in the series, we will uncover the key players in exosome research with updates on the key research initiatives in this exciting and dynamic field. In the meantime, you can read more in our Exosomes Insight Report.

*Updated in January 2024*: 

While the article below was created at the end of 2022, it still has critical insight and emerging trends for the future of scientific R&D.  For the latest trends and breakthroughs, the scientists and experts at CAS recently published a new review on the landscape of scientific trends to watch in 2024: from AI, to emerging materials, our on-going battle against the undruggable proteins, sustainability trends, and more. Additionally, CAS teamed up with experts from Lawrence Livermore National Lab, Oak Ridge National Lab, and The Ohio State University, to reveal the top trends to watch in the year ahead.  If you weren't able to join us for the webinar, see the recording here for the expert's take on the year ahead.  

As published in 2022:

The pace of innovation never slows, and the impact of these scientific breakthroughs will redefine the way we live, work, and connect with the world around us. From space exploration at the largest scale to diagnostics at the single-cell level, these breakthroughs will inspire innovators to push the boundaries of what is possible. 

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A new era of space exploration

Need to be reminded of how incredibly vast our universe is? The first ever photos from the James Webb Space Telescope are awe-inspiring. While this is the most technically advanced and powerful telescope ever created, the learnings about our universe will lead to future missions and exploration for generations ahead. Recently, the newest mission to the moon was launched as NASA’s Artemis Program which will pave the way for a future mission to Mars. This new era of space exploration will drive technological advancements in fields beyond astronautics and stimulate progress in real-world applications like materials, food science, agriculture, and even cosmetics.

A milestone in AI predictions

For decades, the scientific community has chased a greater understanding of relationships between protein functions and 3D structures. In July 2022, Deep Mind revealed that the folded 3D structure of a protein molecule can be predicted from its linear amino-acid sequence using AlphaFold2, RoseTTAFold, and trRosettaX-Single algorithms. The algorithms’ predictions reduced the number of human proteins with unknown structural data from 4,800 to just 29. While there will always be challenges with AI, the ability to predict protein structures has implications across all life sciences. Key challenges in the future include modeling proteins with intrinsic disordered properties and those that change structures by post-translational modifications or to environmental conditions. Beyond protein modeling, AI advancements continue to reshape workflows and expand discovery capabilities across many industries and disciplines.

Developing trends in synthetic biology

Synthetic biology has the potential to redefine synthetic pathways by using engineered biological systems (i.e., microorganisms, for which a large part of the genome or the entire genome has been designed or engineered) to manufacture a range of biomolecules and materials, such as therapeutics, flavors, fabrics, food, and fuels. For example, insulin could be produced without pig pancreas, leather without cows, and spider silk without spiders. The potential in life sciences alone is unbelievable, but when applied to manufacturing industries, synthetic biology could minimize future supply chain challenges, increase efficiency, and create new opportunities for biopolymers or alternative materials with more sustainable approaches. Today, teams use AI-based metabolic modeling, CRISPR tools, and synthetic genetic circuits to control metabolism, manipulate gene expression, and build pathways for bioproduction. As this discipline begins to cross over into multiple industries, the latest developments and emerging trends for metabolic control and engineering challenges are showcased in a 2022 Journal of Biotechnology article.

Single-cell metabolomics set to soar

While much progress has been made in genetic sequencing and mapping, genomics only tells us what a cell is capable of. To have a better understanding of cellular functions, proteomic and metabolomic approaches offer different angles for revealing molecular profiles and cellular pathways. Single-cell metabolomics gives a snapshot of the cellular metabolism within a biological system. The challenge is that metabolomes change rapidly, and sample preparation is critical to understand cell function. Collectively, a series of recent advancements in single-cell metabolomics (from open-sourced techniques, advanced AI algorithms, sample preparations, and new forms of mass spectrometry) demonstrates the ability to run detailed mass spectral analyses. This allows researchers to determine the metabolite population on a cell-by-cell basis, which would unlock enormous potential for diagnostics. In the future, this could lead to the ability to detect even a single cancerous cell in an organism. Combined with new biomarker detection methods, wearable medical devices and AI- assisted data analysis, this array of technologies will improve diagnosis and lives.

New catalysts enable greener fertilizer production

Every year, billions of people depend on fertilizers for the ongoing production of food, and reducing the carbon footprint and expenses in fertilizer production would reshape the impact agriculture has on emissions. The Haber-Bosch process for fertilizer production converts nitrogen and hydrogen to ammonia. To reduce energy requirements, researchers from Tokyo Tech have developed a noble-metal-free nitride catalyst containing a catalytically active transition metal (Ni) on a lanthanum nitride support that is stable in the presence of moisture. Since the catalyst doesn't contain ruthenium, it presents an inexpensive option for reducing the carbon footprint of ammonia production. The La-Al-N support, along with the active metals, such as nickel and cobalt (Ni, Co), produced NH3 at rates similar to conventional metal nitride catalysts. Learn more about sustainable fertilizer production in our latest article.

Advancements in RNA medicine

While the application of mRNA in COVID-19 vaccines garnered lots of attention, the real revolution of RNA technology is just beginning. Recently, a new multivalent nucleoside-modified mRNA flu vaccine was developed. This vaccine has the potential to build immune protection against any of the 20 known subtypes of influenza virus and protect against future outbreaks. Many rare genetic diseases are the next target for mRNA therapies, as they are often missing a vital protein and could be cured by replacing a healthy protein through mRNA therapy. In addition to mRNA therapies, the clinical pipeline has many RNA therapeutic candidates for multiple forms of cancers, and blood and lung diseases. RNA is highly targeted, versatile, and easily customized, which makes it applicable to a wide range of diseases. Learn more about the crowded clinical pipeline and the emerging trends in RNA technologies in our latest CAS Insight Report.

Rapid skeletal transformation

Within synthetic chemistry, the challenge of safely exchanging a single atom in a molecular framework or inserting and deleting single atoms from a molecular skeleton has been formidable. While many methods have been developed to functionalize molecules with peripheral substituents (such as C-H activation), one of the first methods to perform single-atom modifications on the skeletons of organic compounds was developed by Mark Levin’s group at the University of Chicago. This enables selective cleaving of the N–N bond of pyrazole and indazole cores to afford pyrimidines and quinazolines. Further development of skeletal editing methods would enable rapid diversification of commercially available molecules, which could lead to much faster discoveries of functional molecules and ideal drug candidates.

Advancing limb regeneration

Limb loss is projected to affect over 3.6 million individuals per year by 2050. For the longest time, scientists believed the single biggest key to limb regeneration is the presence of nerves. However, work done by Dr. Muneoka and his team demonstrated the importance of mechanical load to digit regeneration in mammals and that the absence of a nerve does not inhibit regeneration. The advancement of limb regeneration was also achieved by researchers at Tufts University who have used acute multidrug delivery, via a wearable bioreactor, to successfully enable long-term limb regeneration in frogs. This early success could potentially lead to larger, more complex tissue re-engineering advances for humans, eventually benefiting military veterans, diabetics, and others impacted by amputation and trauma.

Nuclear fusion generates more net energy with ignition

Nuclear fusion is the process that powers the sun and stars. For decades, the idea of replicating nuclear fusion on earth as a source of energy, in theory, could fulfill all the planet's future energy needs. The goal is to force light atoms to collide so forcefully that they fuse and release more energy than consumed. However, overcoming the electrical repulsion between the positive nuclei requires high temperatures and pressures. Once overcome, fusion releases large amounts of energy, which should also drive the fusion of nearby nuclei. Previous attempts to initiate fusion used strong magnetic fields and powerful lasers but had been unable to generate more energy than they consumed.

Researchers at Lawrence Livermore National Laboratory’s ignition facility reported that the team was able to initiate nuclear fusion, which created 3.15 megajoules of energy from the 2.05 megajoule laser used. While this is a monumental breakthrough, the reality of a functioning nuclear fusion plant powering our grid may still be decades in the making. There are significant implementation hurdles (scalability, plant safety, energy required to generate the laser, wasted by-products, etc.) that must be addressed before this comes to fruition. However, the breakthrough of igniting nuclear fusion is a major milestone that will pave the way for future progress to be built upon this achievement.

For unique insights into an emerging field of science, this CAS Insight Report reveals historical milestones, new applications, and emerging trends found in the CAS Content Collection™. Exosomes are nature’s lipid nanoparticles and their unique physical properties will unlock new applications in drug development, delivery, and diagnostic applications in the future.

In the past few years, lipid nanoparticles have been in the spotlight for their role in mRNA vaccines, but exosomes are often called ‘nature’s lipid nanoparticles’. As a subset of extracellular vesicles, they could reshape the future fields of drug delivery and diagnostics. Their unique physical properties (innate stability, biocompatibility, and the ability to cross the blood-brain barrier) provide many advantages in the future.

This peer-reviewed publication in ACS Nano uses the CAS Content Collection to examine the multifaceted benefits of exosomes in drug development and diagnostics. This includes an examination of the historical breakthroughs, the potential use as a delivery vehicle, and its emerging role in diagnostics. 

Dubbed ‘nature’s lipid nanoparticles’, exosomes are a subset of extracellular vesicles released from cells as part of their normal physiology or under certain pathologies. They are gaining the attention of the scientific community due to their ability to carry messages between cells in the form of proteins, nucleic acids, and other biomolecules. Their promise in therapeutics and diagnostics is garnering interest from both corporate and academic institutions. To predict and fully leverage the potential of the exosome, it is important to understand the depth and breadth of the research landscape.

In this three-part series, we explore the history of exosomes, before describing the latest exosomal research in drug delivery and diagnostics. Using insights from the CAS Content Collection™, we provide a landscape view of recent research advancement on exosome applications, while highlighting the opportunities and challenges in this rapidly expanding area.

The evolution of exosome applications

It was over 50 years ago that researchers first observed minute particulates in human plasma. They found that this material — which they termed “platelet dust” — was lipid-rich and likely to be involved in platelet activation. Yet it was not until the 1980s that these 30–150nm extracellular vesicles were first defined and the name ‘exosomes’ was coined.

Like liposomes, exosomes are comprised of a lipid membrane and an inner aqueous medium. However, exosomes were found to be more complex in structure, containing a large array of proteins and lipids. Produced in the endosomal compartment of most eukaryotic cells, exosomes are subsequently released into the extracellular space by fusion with the plasma membrane. Upon release from the secreting cell, they transmit messages to recipient cells through several mechanisms, including surface receptor interaction, membrane fusion, as well as receptor-mediated endocytosis, phagocytosis, and/or micropinocytosis (Figure 1).

Figure 1. Schematic representation of exosome biogenesis and secretion. The inset shows the molecular constituents of the exosomes. 

Since their initial characterization, further studies have revealed that exosomes are secreted by most viable cell types, including immune cells, intestinal epithelial cells, and neurons. Exosomes are also present in a variety of biological fluids such as blood, urine, saliva, breast milk, amniotic, synovial, cerebrospinal fluids, and even tears.

The exosomal pathway of intercellular traffic plays a significant role in many features of health and disease, including immunity, tissue homeostasis, and regeneration. Exosomes permit efficient intercellular communication and signaling between cells and across biological barriers (including the blood-brain barrier). Exosomes are effective cellular transport systems, capable of shuttling bioactive ‘cargo’ such as proteins, lipids, and nucleic acids. Though exosomes are involved in important physiological activities, they also play a significant role in the pathogenesis of diseases including cancer, cardiovascular and neurodegenerative diseases, and viral infections.

Unique properties of exosome particles

To understand how these small particles can induce such large-scale effects, let’s consider their unique properties. Firstly, they are innately stable due to their lipid bilayer membrane, allowing them to circulate even in the harsh tumor microenvironment. Their lipid bilayer also minimizes immunogenicity and toxicity, supporting their stabilization into the extracellular space. Due to their endogenous origins, exosomes also exhibit high biocompatibility. Finally, exosomes have an excellent tissue/cell penetration capacity. Owing to these properties, exosomes have the potential to overcome several of the limitations associated with other drug delivery systems. Indeed, researchers are beginning to recognize the advantages exosomes hold over other drug carrier systems.

CAS insights into exosome research

An analysis of the CAS Content Collection™ — the largest human-curated collection of published scientific knowledge — has uncovered fascinating insights into the publication trends for exosomes. Currently, there are over 40,000 scientific publications (journal articles and patents) in the CAS Content Collection related to exosomes/extracellular vesicles with a steady, exponential growth over time (Figure 2).

Figure 2. Journal and patent publication trends of exosome research in drug delivery and diagnostics and the association with research funding. (A) Trends in the number of publications related to exosomes in drug delivery and diagnostics, including journal articles and patents. (B) Number of documents originating from organizations in the USA as correlated with the annual NIH funding.

In the last 3–4 years, exosomes have become preferable over lipid nanoparticles (LNPs) as prospective drug carriers and the number of documents, including patents and journal articles, related to exosomes applied in drug delivery has significantly surpassed that of LNPs (Figure 3).

Figure 3. Publication trends of exosomes and lipid nanoparticles applied to drug delivery. (A) Comparison of the trends in the number of publications related to exosomes and lipid nanoparticles. (B) Corresponding percentages of publications related to exosomes (EX) and lipid nanoparticles (LNP) in journal articles (JRN) and patents (PAT) are compared.

The key players in exosome research

According to the CAS Content Collection, the United States, China, Korea, and Japan are leading the way in exosome research, with the largest numbers of published journal articles and patents related to this topic. Patenting activity related to exosomes is also shared equally between corporate and academic institutions, highlighting the universal recognition of their promise in drug delivery, diagnostics, and beyond. MD Healthcare, Codiak Biosciences, and OncoTherapy Science have the largest number of patents of all companies, while the University of California, the University of Louisville, and Zhejiang University are the leading universities and hospitals (Figure 4). In terms of patent distribution, the World Intellectual Property Organization (WIPO) received the most patent applications, followed by the US and China patent offices, the European Patent Office (EPO), and the Korean and Japanese patent offices.

Figure 4. Top patent assignees from companies (A) and universities and hospitals (B) for patents related to exosome applications in drug delivery and diagnostics.

The promise of exosomes

Due to their unique properties and their role in a wide range of physiological and pathological processes, exosomes have emerged as a rising star in drug delivery and diagnostics. The potential applications of these natural nanocarriers are seemingly limitless, with prospective applications in cosmetics and food also being explored.

In our next blog in the series, we’ll delve deeper into the key therapeutic applications of exosomes in drug delivery and diagnostics with further insights from the CAS Content Collection. In the meantime, you can read more about this topic in our Exosome Insight Report.