Introduction: The Scientific Debate and Regulatory Challenges Behind the Terminology

In recent years, exosomes have emerged as one of the most prominent molecular platforms in next-generation regenerative medicine, attracting substantial attention across both the global academic and industrial communities. However, alongside the rapid commercialisation and promotion of exosome-based concepts, a broader scientific term — cell secretome — is increasingly entering the field of research and regulatory consideration.
Although these two concepts are closely interconnected, they are not synonymous. They represent fundamentally different biological entities and, consequently, can lead to markedly different strategic approaches to medical product development and commercialisation.
Of particular concern is the increasingly widespread interchangeability of the terms “exosomes” and “secretome” across both academic and industrial settings. Some studies have treated conditioned medium directly as an exosome preparation, while others have used the two terms almost interchangeably. Such conceptual ambiguity not only compromises the comparability and reproducibility of research, but also creates significant uncertainty during clinical translation and regulatory assessment.
According to a systematic review by Van Delen et al. (2024), only 12.1% of extracellular vesicle (EV) clinical trials reported their isolation methods, while only 36.1% reported characterisation methods. Among more than 200 registered clinical trials worldwide, administered doses have ranged from 10¹⁰ to 10¹⁴ particles (Mizenko et al., 2024). This substantial heterogeneity is, at least in part, rooted in ambiguity surrounding product boundaries: highly purified exosome preparations and more comprehensive secretome-based products differ fundamentally in their chemistry, manufacturing and controls (CMC) requirements and potentially in their regulatory and approval strategies (Foo et al., 2021; Van Delen et al., 2024; Wang et al., 2024).

Building on the framework established in our previous analysis of the Guideline for the Record-filing of Clinical Research on New Technologies for Cell Components and Cell-derived Products (First Edition), as well as our systematic interpretation of the quality framework for exosome products developed by the National Institutes for Food and Drug Control (NIFDC) and the International Society for Extracellular Vesicles (ISEV), this article examines the fundamental scientific differences between the cell secretome and exosomes.
It further explores how these two product concepts may be positioned across two fundamentally different application scenarios — serious healthcare, including clinical medicines and regenerative medicine, and non-serious healthcare, including cosmetics and aesthetic medicine. Finally, regulatory developments and commercial examples from Indonesia, Taiwan, the United States, South Korea and Singapore are considered to provide strategic reference points for Chinese companies seeking to expand internationally.

Core Conceptual Framework: From Extracellular Vesicles to the Cell Secretome

Exosomes/sEVs: Operational Definitions and Molecular Composition under the MISEV2023 Framework

The traditional definition of an exosome describes a nanovesicle approximately 30–150 nm in diameter, surrounded by a lipid bilayer and originating from the endosomal pathway. Specifically, intraluminal vesicles (ILVs) are formed by inward budding within multivesicular bodies (MVBs). Following fusion of the MVB with the plasma membrane, these vesicles are released into the extracellular environment (Kalluri & LeBleu, 2020; van Niel, D'Angelo & Raposo, 2018).

However, under conventional experimental conditions, it is often difficult to demonstrate conclusively that isolated vesicles originated from the endosomal system rather than from shedding of the plasma membrane. In recognition of this methodological limitation, the ISEV MISEV2023 guidelines recommend that researchers use the operational term “small extracellular vesicles” (sEVs), generally referring to vesicles smaller than 200 nm, unless sufficient experimental evidence is available to establish their endosomal origin. This approach is intended to improve scientific rigour and comparability across studies (Welsh et al., 2024).

At the molecular level, exosomes contain three major classes of biomolecules: proteins, nucleic acids and lipids.

Protein composition

Kugeratski et al. (2021), using super-SILAC quantitative proteomics, identified approximately 1,212 quantified proteins, of which 22 were identified as core enriched proteins. Among these, syntenin-1 (SDCBP) exhibited the highest abundance and consistently high expression across different cell types, species and biological fluids. It has therefore been proposed as a potentially more broadly applicable marker than the traditional tetraspanins CD9, CD63 and CD81.

The biological basis for the relevance of syntenin-1 lies in its role in ILV formation, where it interacts with ALIX and links to ESCRT-III. Protein cargo sorting occurs through both ESCRT-dependent and ESCRT-independent pathways, including mechanisms associated with lipid raft microdomains (Mathieu et al., 2019; Lee, Shin & Chae, 2024).

Nucleic acid composition

Exosomes have been reported to carry miRNAs, mRNAs and lncRNAs. However, Jeppesen et al. (2019) reported that exosomes did not contain AGO1–4 proteins, which are core components of the RNA-induced silencing complex (RISC). This finding challenged the conventional view that exosomes are the principal functional carriers of extracellular miRNAs.

The findings suggest that non-vesicular extracellular particles may play a more significant role than previously recognised in the extracellular transport of miRNAs.

Lipid composition

At the membrane level, exosomes are characteristically enriched in sphingomyelin, cholesterol and ceramide. Ceramide can directly promote ILV formation by inducing changes in membrane curvature. The lipid composition also has a significant influence on the biophysical characteristics and stability of exosomes (van Niel, D'Angelo & Raposo, 2018; Lee, Shin & Chae, 2024).

Isolation and characterisation

At the manufacturing level, tangential flow filtration (TFF) combined with size-exclusion chromatography (SEC) has emerged as a preferred combination for GMP exosome production.

Visan et al. (2022) systematically evaluated different approaches and demonstrated that TFF–SEC was superior to ultracentrifugation (UC) in maintaining vesicle integrity and functional activity. The mechanical forces generated during ultracentrifugation at up to 100,000 × g can contribute to vesicle aggregation and membrane damage.

Importantly, no single isolation method can completely eliminate all contaminants. Consequently, multi-step purification strategies are generally considered necessary to achieve an appropriate balance between purity, recovery and product functionality (Liangsupree, Multia & Riekkola, 2021).

MISEV2023 recommends a minimum characterisation framework incorporating three categories of markers:

1. Positive transmembrane markers, such as CD9, CD63 and CD81;
2. Positive cytosolic markers, such as syntenin-1, ALIX and TSG101; and
3. Negative markers, such as calnexin and albumin, to demonstrate the absence of cellular or soluble protein contamination.

These molecular analyses should be complemented by at least two orthogonal physical characterisation techniques, such as nanoparticle tracking analysis (NTA) and transmission electron microscopy (TEM) (Welsh et al., 2024).

Cell Secretome: Definition, Three Major Components and Manufacturing Considerations

Knecht et al. (2023) define the secretome as “the complete collection of proteins actively released into the extracellular space by cells, tissues or organisms”. Han et al. (2022) further expanded this concept to encompass proteins, lipids, nucleic acids and extracellular vesicles (EVs), which collectively regulate intercellular communication and the tissue microenvironment through paracrine and endocrine mechanisms.

The complete protein profile of the MSC secretome has been reported to contain more than 2,000 proteins (Al-Sharabi et al., 2023). This contrasts with approximately 1,200–1,600 proteins reported within the core exosome proteome (Kugeratski et al., 2021), illustrating a substantial difference in compositional complexity and providing a material basis for the functional distinction between the two product types.

Table 1. Three Major Components of the Secretome and Their Functional Characteristics

Data sources: Drobiova et al. (2023); Han et al. (2022); Al-Sharabi et al. (2023); Niada et al. (2021)

These three categories collectively form a multi-layered therapeutic network.

Soluble factors can directly activate receptors on target cells without requiring cellular internalisation, allowing relatively rapid biological responses. EVs, including exosomes, protect their molecular cargo within a lipid membrane, thereby providing protection against extracellular degradation and potentially enabling a degree of targeting. Meanwhile, ECM proteins contribute structural support to the regenerative microenvironment and can activate integrin-mediated signalling pathways.

Niada et al. (2021) directly compared the proteomes of conditioned medium (CM) and EVs derived from human adipose stem cells using LC-MS/MS. The study identified 1,977 proteins in total and found 68 factors specific to CM and 201 factors specific to EVs. Principal component analysis (PCA) clearly separated CM and EVs into two distinct proteomic groups. CM was enriched in proteins associated with secretory pathways, whereas EVs were characterised by proteins associated with GTPase activity and ribosomal functions.

These findings provide direct evidence that soluble secreted proteins and vesicle-associated proteins represent distinct functional compartments.

Foo et al. (2021) therefore proposed that the therapeutic effects of the complete secretome may be greater than the simple sum of the effects of its individual components — “the whole secretome may be greater than the sum of its parts”. The potential synergy between soluble factors and vesicular cargo provides an important biological rationale for maintaining a clear distinction between the secretome and purified exosome products.

Manufacturing considerations

At the manufacturing level, conditioned medium (CM) represents the standard experimental form of the secretome and embodies the concept of cell-free therapy. By eliminating the need to administer viable cells, this approach may avoid certain risks associated with cell transplantation, including potential tumorigenicity and immune rejection (Dangerfield & Metzner, 2026).

However, secretome composition is highly dependent on multiple upstream parameters, including:

• cell source, such as bone marrow, umbilical cord or adipose tissue;
• culture configuration, including 2D versus 3D systems;
• oxygen conditions, including normoxia versus hypoxia; 
• harvest timing.

Proteomic analysis by Shin et al. (2021) demonstrated that secretomes from four different MSC sources shared only 181 core proteins. The number of differentially expressed proteins substantially exceeded the number of common proteins, highlighting the importance of cell-source selection for specific therapeutic indications.

Hypoxic preconditioning at 1–5% O₂ can further enhance the secretion of angiogenic and neurotrophic factors. At larger scales, stirred suspension bioreactors represent a promising platform for reproducible and scalable secretome production (Bari et al., 2023).

Establishing a comprehensive CMC framework — including cell-source identification, documentation of culture parameters and verification of batch-to-batch consistency — is therefore a central requirement for transitioning the secretome from a research material into a regulated therapeutic product (Bari et al., 2023; Chinnadurai, 2023).

From a conceptual perspective, the relationship can be summarised as:

Cell Secretome (Secretome) ⊇ Extracellular Vesicles (EVs) ⊇ Exosomes/sEVs

Key Differences Between the Cell Secretome and Exosomes/sEVs

Compositional Complexity and Potential Synergistic Therapeutic Effects

Following multiple purification steps, exosomes/sEVs represent a relatively concentrated and compositionally narrower subfraction of the cellular secretome. Their biological activity is primarily associated with vesicle-associated membrane proteins, luminal proteins such as HSP70 and HSP90, and nucleic acid cargo, particularly microRNAs (Mathieu et al., 2019).

Several studies have demonstrated that exosomes can transfer functional microRNAs to recipient cells, resulting in changes in gene expression. This mechanism represents an important biological distinction from soluble growth factors and cytokines (Kalluri & LeBleu, 2020).

By contrast, incompletely separated cell secretome preparations — including conditioned medium or partially purified culture supernatant — retain both soluble growth factors and EV-associated components. Several key studies have demonstrated that stem-cell-derived conditioned medium can produce stronger protective or regenerative effects than either individual component alone in animal models of myocardial infarction and neurological injury, suggesting that multi-component secretome preparations may offer a broader therapeutic signalling profile (Ranganath et al., 2012).

However, this compositional complexity also creates substantial challenges in terms of process control, batch-to-batch consistency and comprehensive quality characterisation.

Li et al. (2022) directly compared the functional effects of sEVs and CM in models of wound healing and bone regeneration. CM demonstrated stronger pro-angiogenic and cell-migration effects, whereas sEVs showed greater immunomodulatory and anti-inflammatory activity. In the bone-regeneration model, sEVs demonstrated stronger induction of osteogenic differentiation, while CM provided broader regenerative signalling coverage.

This illustrates a complementary distinction between “precision” and “breadth” rather than a simple hierarchy between the two modalities.

At the level of immune regulation, Leñero et al. (2022) found that exosomes from specific MSC subpopulations were enriched in immunomodulatory miRNAs, including miR-21-5p, miR-146a-5p and miR-155-5p. These miRNAs can target pathways including TLR/NF-κB and JAK-STAT, thereby suppressing M1 macrophage polarisation.

By comparison, soluble cytokines within the complete secretome, including IL-10, TGF-β and PGE2, can simultaneously influence T cells, B cells, NK cells and dendritic cells, potentially producing a broader remodelling effect on the immune microenvironment (Dangerfield & Metzner, 2026).

This complementary relationship between targeted regulation and multi-dimensional signalling provides a biological basis for differentiated indication positioning between the two product categories.

Divergent Manufacturing Strategies

Exosome/sEV manufacturing generally consists of two major stages.
The first is the upstream cell-culture stage, during which the culture conditions need to be carefully controlled. During the harvest phase, the culture medium may need to be switched to a formulation free from exogenous EVs and other nanoparticles to minimise background contamination and improve the purity of the final product.
The second is the downstream purification stage, which may involve differential ultracentrifugation, size-exclusion chromatography, tangential flow filtration and other purification technologies.
Such purification processes substantially reduce soluble protein content in the final preparation, producing a product that is more closely centred on the vesicular fraction. This can facilitate quantitative quality control and the development of more standardised product specifications.
By comparison, cell secretome products generally undergo either no purification or only limited purification. A typical process may involve microfiltration to remove cells and large debris, followed by ultrafiltration for concentration, while retaining a relatively comprehensive representation of the secreted components.

This manufacturing strategy is comparatively straightforward and may require lower equipment investment and shorter production cycles than highly purified sEV products.
Such cost advantages may be particularly relevant when considering applications in cosmetics and aesthetic medicine, where regulatory requirements and product positioning can differ substantially from those applicable to therapeutic medicinal products.

Differentiated Quality Control Requirements

According to MISEV2023 (Welsh et al., 2024) and the systematic analysis by Na et al. (2026) of exosome product quality evaluation under the Chinese regulatory framework, highly purified sEV products require a CQA framework covering several core attributes.

These include:

• particle number and size distribution, measured by NTA;
• vesicle membrane integrity, assessed through fluorescence-based methods or DLS;
• characteristic surface markers, including CD63, CD81 and CD9, quantified through Western blotting or flow-based methods;
• nucleic acid cargo composition, where applicable;
• process-related impurities, including residual host-cell proteins, nucleic acids and culture-medium components;
• sterility;
• mycoplasma;
• endotoxin; 
• biological activity and potency.

The quality-control requirements for secretome products are more complex. In addition to EV-related parameters, where EVs form part of the product, secretome products require characterisation of the soluble protein profile, potentially through cytokine arrays or other quantitative and semi-quantitative methods.

At present, however, there is no universally accepted international quality standard for cell secretome products, and relevant methodologies remain under development. This represents one of the principal regulatory challenges for secretome-based products entering serious healthcare applications.

Table 2. Comparison of Quality-Control Requirements for Exosomes and Complete Secretome Products
Data sources: Welsh et al. (2024); Humbert et al. (2025); Bari et al. (2023); Chinnadurai (2023); Wang et al. (2024)

Chinnadurai (2023) recommends a “measurement matrix” approach.
For purified exosomes, both particle characteristics and specific functional activity should be evaluated. For secretome products, total protein content and key functional factors should be quantitatively assessed alongside biological activity.
The differences illustrated in Table 2 should not be interpreted as indicating that one product type is inherently superior to the other. Rather, they demonstrate that the two modalities have different quality-control requirements arising from their distinct biological compositions.
Exosomes can provide more precisely defined and potentially standardisable functional modules, whereas the secretome provides a broader spectrum of therapeutic molecules. Selection of the appropriate clinical-development pathway should therefore consider the intended indication, regulatory environment and feasibility of industrial-scale manufacturing.

Table 3. Key Comparison Between the Cell Secretome and Exosomes/sEVs

Regulatory Perspective: Where Do Secretome and Exosome Products Fit?

As secretome- and exosome-based technologies move towards clinical and commercial applications, an important question is how regulators define and classify these products.
The regulatory landscape remains fragmented, with different jurisdictions taking different approaches based on factors such as product composition, intended use, manufacturing process and proposed claims. This is particularly relevant for secretome products, for which regulatory precedent remains limited and no universally harmonised product definition currently exists.
China provides an instructive example of this evolving landscape.

The Guideline for the Record-filing of Clinical Research on New Technologies for Cell Components and Cell-derived Products (First Edition) issued by China's National Health Commission (NHC) (国家卫生健康委员会, 2024) does not explicitly define “cell components” or “cell-derived products”. From a biological perspective, this broader category could potentially encompass products generated through cellular activity, including purified exosomes/sEVs, microvesicles and other EVs, as well as conditioned-medium-based secretome products.
This leaves potential scope for secretome-based products to be considered within the broader cell-derived product framework. Importantly, this does not imply a lower regulatory threshold. Regardless of whether the product is a purified vesicle preparation or a broader secretome, developers still need to establish appropriate product identity, manufacturing controls, quality, safety and biological activity.
China's regulatory direction has become clearer in recent years. In June 2025, the Center for Drug Evaluation (CDE) of China's National Medical Products Administration (NMPA) issued the Scope Definition and Classification Interpretation of Advanced Therapy Medicinal Products (ATMPs) (Draft for Comment), which explicitly included EVs within the regulatory scope of ATMPs (Na et al., 2026). In 2024, the National Center for ADR Monitoring (NIFDC) also recommended that exosomes should not be regulated as medical devices, further narrowing the potential medical-device pathway.

Conclusion

The distinction between cell secretome and exosomes/sEVs goes beyond terminology, reflecting fundamental differences in biological composition, manufacturing, quality control and regulatory considerations.
The secretome encompasses a broad range of soluble factors, extracellular vesicles and other secreted components. This complexity may contribute to its therapeutic potential, but also creates challenges in product characterisation, process control and batch consistency. Exosomes/sEVs, by contrast, represent a more defined vesicular fraction that can be characterised using particle-based and molecular methods, although achieving high purity requires more complex downstream processing and higher manufacturing costs.
These differences also influence regulatory strategy. As frameworks for cell-derived products continue to evolve, including developments in China, developers need to define their product clearly before determining the appropriate regulatory pathway.
Ultimately, the choice between secretome and exosomes/sEVs depends on the intended indication, application, manufacturing strategy and regulatory requirements. For serious healthcare applications, CMC control, potency, safety, consistency and clinical evidence remain central. For non-serious healthcare applications, factors such as manufacturing cost, product claims and applicable regulations may carry greater weight.

The next article will explore the global commercialisation landscape, examining product positioning, regulatory developments and international market examples to provide a practical framework for companies evaluating global expansion strategies.

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