the widespread use of LAMP-2B-based engineering for loading proteins of interest onto the surface of exosomes. Beyond its role in antigen exposure, this method has been employed to confirm the targeting capabilities of exosomes, depending on the selected protein for display. Thus, LAMP-2B constructs fused with a rabies viral glycoprotein peptide, known to direct rabies virus neurotropism, effectively enabled the production of exosomes that reached the brain [262]. If a ligand is yet to be identified for a tissue- or cell-specific receptor, protein libraries can be screened or biopanned using high-throughput phage display methods. Upon finding a peptide with adequate affinity for the target receptor, it can be fused to LAMP-2B and expressed on exosomes. Subsequent in vivo experiments can be performed to assess whether exosomes display the expected tropism. This strategy has been adopted to specifically target exosomes to hepatic stellate cells, which are relevant targets in liver fibrosis [263].

Numerous adaptations of exosome display, based on the expression of transgenes, have been developed. As previously discussed, specific viral proteins exploit the exosome biogenesis pathway to facilitate virus budding. It has been shown that transmembrane subunits of viral envelope proteins, including those of HIV, can interact with components of the ESCRT machinery, such as TSG101 [264]. These properties, which are found in the proteins of various viruses (e.g., the VSV-G protein or the Nef protein of HIV), have been exploited to direct proteins of interest to exosomes [265]. In order to assess the exosomal addressing capabilities of viral proteins, a vector encoding the CD8 ectodomain, used as a neutral reporter, fused with the cytosolic domain of the transmembrane envelope protein (CDTM-Env) derived from the bovine leukemia virus (BLV) was employed. Cells transfected with this construct successfully produced exosomes expressing the chimeric protein. This finding indicates the potential utilization of specific domains within certain viral proteins for directing antigens into exosomes [266]. Exosome engineering likely needs to be adapted to the specific type of antigen intended for expression. Comparisons of reproducibility and yields across various exosome display systems, depending on the constructs and techniques used to introduce transgenes into cells, should be conducted to identify the optimal technique.

In addition to surface display engineering of exosomes, another strategy termed "cloaking" has been developed to make exosomes presenting scaffolds for proteins of interest. This approach involves the ex vivo modification of exosome surfaces to enhance their targeting precision toward recipient cells. The proof of concept was put forth using cardiosphere-derived cells exosomes, cloaked with a phospholipid membrane anchor and streptavidin. The coating with streptavidin molecules enables the binding of any biotinylated molecule at the surface of exosomes, including tissue-specific antibodies and homing peptides. This technology could be beneficial for the development of exosome-based vaccines, as it would allow the precise targeting of antigens to APCs [267].

Furthermore, the lipid bilayer of exosomes holds substantial potential for anchoring lipid conjugates (Figure 5B). It is composed of different lipids like cholesterol, ceramide, and phosphatidylethanolamine derivatives that serve as lipid anchors in regions called lipid rafts, ensuring the attachment of functional entities to the exosome membrane. A recent study demonstrated that the incubation of fluorophore-bound dioleoyl phosphatidylethanolamine (DOPE) with EVs leads to its effective anchoring to the EV membrane. This approach could be used to activate the immune response when the fluorochrome is replaced by an antigen of interest, which could subsequently be used as in a vaccine [268]. Furthermore, lipids of the exosomal membrane can be covalent protein-anchoring systems, which is the case for glycosylphosphatidylinositol (GPI)-anchored proteins. Thus, several studies have reported the possibility of efficiently addressing proteins of interest on the surface of exosomes by introducing in cells transgenes that drive the expression of chimeric (GPI)-anchored proteins [269,270].

The collective findings suggest that loading exosomes with tailored antigens through different strategies appears to be a viable approach for the development of vaccines targeting a range of diseases and pathogens, including flaviviruses.
the widespread use of LAMP-2B-based engineering for loading proteins of interest onto the surface of exosomes. Beyond its role in antigen exposure, this method has been employed to confirm the targeting capabilities of exosomes, depending on the selected protein for display. Thus, LAMP-2B constructs fused with a rabies viral glycoprotein peptide, known to direct rabies virus neurotropism, effectively enabled the production of exosomes that reached the brain [262]. If a ligand is yet to be identified for a tissue- or cell-specific receptor, protein libraries can be screened or biopanned using high-throughput phage display methods. Upon finding a peptide with adequate affinity for the target receptor, it can be fused to LAMP-2B and expressed on exosomes. Subsequent in vivo experiments can be performed to assess whether exosomes display the expected tropism. This strategy has been adopted to specifically target exosomes to hepatic stellate cells, which are relevant targets in liver fibrosis [263].

Numerous adaptations of exosome display, based on the expression of transgenes, have been developed. As previously discussed, specific viral proteins exploit the exosome biogenesis pathway to facilitate virus budding. It has been shown that transmembrane subunits of viral envelope proteins, including those of HIV, can interact with components of the ESCRT machinery, such as TSG101 [264]. These properties, which are found in the proteins of various viruses (e.g., the VSV-G protein or the Nef protein of HIV), have been exploited to direct proteins of interest to exosomes [265]. In order to assess the exosomal addressing capabilities of viral proteins, a vector encoding the CD8 ectodomain, used as a neutral reporter, fused with the cytosolic domain of the transmembrane envelope protein (CDTM-Env) derived from the bovine leukemia virus (BLV) was employed. Cells transfected with this construct successfully produced exosomes expressing the chimeric protein. This finding indicates the potential utilization of specific domains within certain viral proteins for directing antigens into exosomes [266]. Exosome engineering likely needs to be adapted to the specific type of antigen intended for expression. Comparisons of reproducibility and yields across various exosome display systems, depending on the constructs and techniques used to introduce transgenes into cells, should be conducted to identify the optimal technique.

In addition to surface display engineering of exosomes, another strategy termed "cloaking" has been developed to make exosomes presenting scaffolds for proteins of interest. This approach involves the ex vivo modification of exosome surfaces to enhance their targeting precision toward recipient cells. The proof of concept was put forth using cardiosphere-derived cells exosomes, cloaked with a phospholipid membrane anchor and streptavidin. The coating with streptavidin molecules enables the binding of any biotinylated molecule at the surface of exosomes, including tissue-specific antibodies and homing peptides. This technology could be beneficial for the development of exosome-based vaccines, as it would allow the precise targeting of antigens to APCs [267].

Furthermore, the lipid bilayer of exosomes holds substantial potential for anchoring lipid conjugates (Figure 5B). It is composed of different lipids like cholesterol, ceramide, and phosphatidylethanolamine derivatives that serve as lipid anchors in regions called lipid rafts, ensuring the attachment of functional entities to the exosome membrane. A recent study demonstrated that the incubation of fluorophore-bound dioleoyl phosphatidylethanolamine (DOPE) with EVs leads to its effective anchoring to the EV membrane. This approach could be used to activate the immune response when the fluorochrome is replaced by an antigen of interest, which could subsequently be used as in a vaccine [268]. Furthermore, lipids of the exosomal membrane can be covalent protein-anchoring systems, which is the case for glycosylphosphatidylinositol (GPI)-anchored proteins. Thus, several studies have reported the possibility of efficiently addressing proteins of interest on the surface of exosomes by introducing in cells transgenes that drive the expression of chimeric (GPI)-anchored proteins [269,270].

The collective findings suggest that loading exosomes with tailored antigens through different strategies appears to be a viable approach for the development of vaccines targeting a range of diseases and pathogens, including flaviviruses.
6.4. *Ongoing Exosome-Based Vaccine Strategies against Viruses*

Thanks to the wide range of available techniques for engineering exosomes into
antigen-presenting platforms, exosome-based candidate vaccines against several viruses
have been researched and have undergone several phases of validation of their suitability.
A trial was conducted with exosomes modified to carry HCV full-length NS3 protein. The
modified exosomes proved immunogenic when injected into mice, which was confirmed
by the detection of NS3-specific memory CD8+ T cells [271]. Anticoli et al. have also
demonstrated the efficacy of engineering exosomes with DNA vectors expressing stable
fusion products of viral antigens fused to an exosome-anchoring protein. Assayed viral
antigens included those of the Ebola virus, influenza virus, Crimean–Congo hemorrhagic
fever, and West Nile virus. Upon injection in mice models, these vectors have been shown
to elicit a potent antigen-specific CD8+ T-cell response, which was further supported by
their cytotoxic activity against antigen-expressing cells [272].

More recently, in the face of the global COVID-19 crisis, there has been a flurry of
research into innovative vaccination strategies exploiting the exosome approach [273,274].
Two of these strategies are summarized in Figure 6. One strategy, following the popular-
ization of mRNA vaccines, strove to turn exosomes into mRNA vectorization tools. The
use of exosomes to vectorize mRNAs for vaccine purposes has been successfully tested
and shown to promote an immune response [275]. Thus, for example, Popowski et al.
developed a system based on lung-derived exosomes carrying SARS-CoV-2 Spike mRNA.
These exosomes have shown extensive distribution in the bronchioles and parenchyma
of mice. In addition, they elicited significant immunoglobulin G (IgG) and secretory IgA
(SIgA) production, demonstrating the relevance of such an approach for obtaining a good
adaptive immune response [276]. Other work showed that bovine-milk-derived exosomes
loaded with mRNA encoding the SARS-CoV-2 receptor-binding domain (RBD) stimulated
the production of neutralizing antibodies against RBD in mice [277].

<figure><img src="image_10.png" /><figcaption>**Figure 6.** Exosomes modified according to two strategies' have been proposed as candidate vaccines against SARS-CoV-2. They are either designed to carry viral mRNA or engineered to expose a viral antigen, such as the Spike RBD. Both of these candidate vaccines demonstrated protection against SARS-CoV-2 infection in mice.</figcaption></figure>

It is noteworthy that research on exosome-based vaccines against coronaviruses has
been ongoing since 2007 [278]. Thus, it was demonstrated that exosomes containing the
Spike (S) proteins of SARS-CoV, the transmembrane and cytoplasmic domains of which
were replaced with those of the vesicular stomatitis virus glycoprotein (VSV-G), induced
## 6.4. Ongoing Exosome-Based Vaccine Strategies against Viruses

Thanks to the wide range of available techniques for engineering exosomes into antigen-presenting platforms, exosome-based candidate vaccines against several viruses have been researched and have undergone several phases of validation of their suitability. A trial was conducted with exosomes modified to carry HCV full-length NS3 protein. The modified exosomes proved immunogenic when injected into mice, which was confirmed by the detection of NS3-specific memory CD8+ T cells [271]. Anticoli et al. have also demonstrated the efficacy of engineering exosomes with DNA vectors expressing stable fusion products of viral antigens fused to an exosome-anchoring protein. Assayed viral antigens included those of the Ebola virus, influenza virus, Crimean-Congo hemorrhagic fever, and West Nile virus. Upon injection in mice models, these vectors have been shown to elicit a potent antigen-specific CD8+ T-cell response, which was further supported by their cytotoxic activity against antigen-expressing cells [272].

More recently, in the face of the global COVID-19 crisis, there has been a flurry of research into innovative vaccination strategies exploiting the exosome approach [273,274]. Two of these strategies are summarized in Figure 6. One strategy, following the popularization of mRNA vaccines, strove to turn exosomes into mRNA vectorization tools. The use of exosomes to vectorize mRNAs for vaccine purposes has been successfully tested and shown to promote an immune response [275]. Thus, for example, Popowski et al. developed a system based on lung-derived exosomes carrying SARS-CoV-2 Spike mRNA. These exosomes have shown extensive distribution in the bronchioles and parenchyma of mice. In addition, they elicited significant immunoglobulin G (IgG) and secretory IgA (SIgA) production, demonstrating the relevance of such an approach for obtaining a good adaptive immune response [276]. Other work showed that bovine-milk-derived exosomes loaded with mRNA encoding the SARS-CoV-2 receptor-binding domain (RBD) stimulated the production of neutralizing antibodies against RBD in mice [277].

<figure><img src="image_9.png" /><figcaption>**Figure 6.** Exosomes modified according to two strategies' have been proposed as candidate vaccines against SARS-CoV-2. They are either designed to carry viral mRNA or engineered to expose a viral antigen, such as the Spike RBD. Both of these candidate vaccines demonstrated protection against SARS-CoV-2 infection in mice.</figcaption></figure>

It is noteworthy that research on exosome-based vaccines against coronaviruses has been ongoing since 2007 [278]. Thus, it was demonstrated that exosomes containing the Spike (S) proteins of SARS-CoV, the transmembrane and cytoplasmic domains of which were replaced with those of the vesicular stomatitis virus glycoprotein (VSV-G), induced
high levels of neutralizing antibodies [278]. In the context of the COVID-19 pandemic, this strategy of modifying exosomes as antigen-presenting platforms has been relaunched by a growing number of start-ups and private or semi-private biotech companies worldwide, interested in developing extracellular vesicle-based therapies and virus- and adjuvant-free vaccines based on recombinant exosomes [279]. In this respect, an extremely promising vaccine candidate that has passed pre-clinical trials proposes the inhalation delivery of pulmonary exosomes, which carry the recombinant SARS-CoV-2 RBD. The process of this second strategy, related to the use of exosomes as an antigen-presenting device, is described in Figure 6. The engineered and purified exosomes had the advantage of being remarkably stable after lyophilization. They have been shown both to enhance RBD retention in the airways and lung parenchyma, and to induce the production of RBD-specific IgG antibodies in mice. They also enabled a mucosal IgA response and an effective T-cell response that was able to clear the virus in a challenge test [280]. To the best of our knowledge, this promising work has given new momentum to ongoing research by start-ups into exosome-based vaccine strategies against the Chikungunya, Zika, Dengue, and West Nile viruses.

Although vaccines confer the host with durable immunity, pathogens are notorious for evading the immune system through antigenic variation, a challenge that is usually overcome with the use of cocktails and multi-epitope vaccines. In this regard, exosomes could be engineered to present multiple antigens. During the SARS-CoV-2 epidemic, all commercially available vaccines targeted the S glycoprotein, which was consequently subjected to a strong selective pressure. The rapid mutation rate gave rise to numerous variants that could escape the vaccine-induced immunity, notably omicron variants. In contrast, other viral proteins, such as the nucleocapsid (N) protein, are less prone to mutations. In order to broaden immunity against coronaviruses, Cacciottolo et al. have devised a bivalent exosome-based vaccine against delta SARS-CoV-2. Using cell lines that stably expressed both S and N proteins, they produced S- and N-laden exosomes. Upon injection in mice and rabbits, these exosomes elicited a robust T-cell response and significant titers of neutralizing antibodies. Strikingly, these antibodies demonstrated cross-neutralization abilities against omicron variants. Interestingly, exosomes were injected without adjuvants, and low amounts of viral proteins sufficed to produce an efficient response. Finally, the vaccine was regarded as safe and only two shots were required to achieve immunity [274].

The aforementioned strategies exemplify the promising applications of exosomes in the field of vaccinology. However, exosome-based vaccines against viruses are still in their infancy and, so far, they have not produced any widely approved formulations. Further studies must be performed to assess their efficacy and innocuity, but current developments are nonetheless encouraging.

## 7. Challenges and Issues

Exosomes show promise in advancing medical treatments, such as cell-free therapies, drug nanocarriers, or vaccines, offering targeted and efficient options. However, there are still many difficulties to overcome.

Regarding exosome-based vaccines, a challenge arises in the formulation process, which requires the production of consistent batches of exosomes, each containing the adequate levels of antigen necessary for effective protection [281]. Moreover, a large-scale and efficient source of exosomes, such as high-throughput cellular systems, must be considered and carefully thought-out, to meet the growing demand. This consideration becomes particularly significant in light of the recent SARS-CoV-2 epidemic, emphasizing the urgency for swift and sustained vaccine availability to achieve effective herd immunity. Simultaneously, it is crucial to manage the immunogenicity of exogenous components, namely, those derived from the cell line used to produce exosomes. Another limitation is the heterogeneity of exosomes, which contain a large number of diverse proteins and materials from host cells, making it challenging to customize their cargoes compared to liposomes [282]. While immunogens and adjuvants can be easily packaged in liposomes, incorporating
high levels of neutralizing antibodies [278]. In the context of the COVID-19 pandemic, this strategy of modifying exosomes as antigen-presenting platforms has been relaunched by a growing number of start-ups and private or semi-private biotech companies worldwide, interested in developing extracellular vesicle-based therapies and virus- and adjuvant-free vaccines based on recombinant exosomes [279]. In this respect, an extremely promising vaccine candidate that has passed pre-clinical trials proposes the inhalation delivery of pulmonary exosomes, which carry the recombinant SARS-CoV-2 RBD. The process of this second strategy, related to the use of exosomes as an antigen-presenting device, is described in Figure 6. The engineered and purified exosomes had the advantage of being remarkably stable after lyophilization. They have been shown both to enhance RBD retention in the airways and lung parenchyma, and to induce the production of RBD-specific IgG antibodies in mice. They also enabled a mucosal IgA response and an effective T-cell response that was able to clear the virus in a challenge test [280]. To the best of our knowledge, this promising work has given new momentum to ongoing research by start-ups into exosome-based vaccine strategies against the Chikungunya, Zika, Dengue, and West Nile viruses.

Although vaccines confer the host with durable immunity, pathogens are notorious for evading the immune system through antigenic variation, a challenge that is usually overcome with the use of cocktails and multi-epitope vaccines. In this regard, exosomes could be engineered to present multiple antigens. During the SARS-CoV-2 epidemic, all commercially available vaccines targeted the S glycoprotein, which was consequently subjected to a strong selective pressure. The rapid mutation rate gave rise to numerous variants that could escape the vaccine-induced immunity, notably omicron variants. In contrast, other viral proteins, such as the nucleocapsid (N) protein, are less prone to mutations. In order to broaden immunity against coronaviruses, Cacciottolo et al. have devised a bivalent exosome-based vaccine against delta SARS-CoV-2. Using cell lines that stably expressed both S and N proteins, they produced S- and N-laden exosomes. Upon injection in mice and rabbits, these exosomes elicited a robust T-cell response and significant titers of neutralizing antibodies. Strikingly, these antibodies demonstrated cross-neutralization abilities against omicron variants. Interestingly, exosomes were injected without adjuvants, and low amounts of viral proteins sufficed to produce an efficient response. Finally, the vaccine was regarded as safe and only two shots were required to achieve immunity [274].

The aforementioned strategies exemplify the promising applications of exosomes in the field of vaccinology. However, exosome-based vaccines against viruses are still in their infancy and, so far, they have not produced any widely approved formulations. Further studies must be performed to assess their efficacy and innocuity, but current developments are nonetheless encouraging.

## 7. Challenges and Issues

Exosomes show promise in advancing medical treatments, such as cell-free therapies, drug nanocarriers, or vaccines, offering targeted and efficient options. However, there are still many difficulties to overcome.

Regarding exosome-based vaccines, a challenge arises in the formulation process, which requires the production of consistent batches of exosomes, each containing the adequate levels of antigen necessary for effective protection [281]. Moreover, a large-scale and efficient source of exosomes, such as high-throughput cellular systems, must be considered and carefully thought-out, to meet the growing demand. This consideration becomes particularly significant in light of the recent SARS-CoV-2 epidemic, emphasizing the urgency for swift and sustained vaccine availability to achieve effective herd immunity. Simultaneously, it is crucial to manage the immunogenicity of exogenous components, namely, those derived from the cell line used to produce exosomes. Another limitation is the heterogeneity of exosomes, which contain a large number of diverse proteins and materials from host cells, making it challenging to customize their cargoes compared to liposomes [282]. While immunogens and adjuvants can be easily packaged in liposomes, incorporating
desired components into exosomes has proven challenging at times [283]. In addition to
the advantages afforded by standardized liposomes for the delivery of therapeutics, the
“exosome” strategy is being challenged by other strategies for the custom development
of delivery systems based, for example, on bacteriophage virus-like particles (VLPs) [284]
or other biomimetic platforms [285]. Future research on exosomes for vaccine purposes
will have to establish a comparison with these other types of nano-platforms, particularly
in preclinical studies. Furthermore, when exosomes are injected into a patient, they may
compete with their endogenous counterparts, potentially affecting the desired therapeutic
effects [282], or interfering with intercellular communication networks. They may also bind
to competitive ligands instead of cell receptors [286]. Exosomes harvested from DCs could
hold the best vaccine potential, as they naturally express antigen-presentation molecules.
This strategy has already proven its relevance in oncology, with DC exosome-based vac-
cines that have passed both preclinical and clinical phases, demonstrating good tolerance
and safety [287,288]. On the downside, the many clinical trials carried out in recent years
with exosome-based cancer immunotherapies have not always produced the expected
results, prompting further research into the immune mechanisms controlled by exosomes
in vivo [289].

Finally, ethical considerations surrounding safety, informed consent, and unpre-
dictable consequences must be addressed. Rigorous testing, transparency in research,
and clear patient communication are essential. Balancing innovation with ethical standards
is paramount to harness the full potential of exosomes in medicine. The evolution of
guidelines to ensure responsible and beneficial applications is strikingly evident.

8. Concluding Remarks

The global health crisis caused by SARS-CoV-2 has reinforced the need to diversify vaccine strategies against viral infections. This, in turn, has renewed interest in exosomes as particularly attractive nanocarriers. We therefore set out to review the literature on the biology of exosomes, which mediate signaling between cells and play a key role in both physiological and pathological processes. We pointed out their considerable relevance as potential biomarkers and diagnostic, and therapeutic tools in contemporary medicine. Their role in viral infections is increasingly studied, and we have pointed out that it is often dual, complicating the prospects for their therapeutic usage. However, significant advances in the engineering of these vesicles for the custom loading of proteins or RNAs confirm that they are interesting nano-vectors of new therapeutic molecules. Likewise, exosomes could benefit from the innovative design of vaccines, unveiling novel strategies for viral infection control. The recent demonstration of their efficacy in preclinical models strengthens their use as original platforms for antigen presentation or mRNA vectorization systems. However, uncertainties remain on several aspects such as the choice of exosome-producing cells, engineering methods, standardized production, the safety of administration, and ethical considerations. Nevertheless, this paves the way for the exploration of new approaches to control flavivirus infections, such as DENV or ZIKV, for which vaccine design has become challenging. The transition to clinical trials will, of course, be necessary to validate these approaches and, hopefully, propel exosome-based therapies from bench to bedside.

**Author Contributions:** Conceptualization, D.E.S., A.M., M.K., A.L., U.H., G.L., W.V. and P.K.-T.; Methodology, resources, and writing—original draft preparation, D.E.S., A.M., M.K., A.L., U.H., G.L., W.V. and P.K.-T.; Figure drawings, D.E.S., G.L. and M.K.; Writing—review and editing, D.E.S., A.M. and P.K.-T.; Visualization, P.K.-T. and W.V.; Supervision, P.K.-T.; Funding acquisition, W.V. and P.K.-T. All authors have read and agreed to the published version of the manuscript.

**Funding:** D.E.S. has PhD degree scholarships from Réunion University (Ecole doctorale STS) funded by DIRED/2021-1115 Région Réunion, and M.K. has a PhD degree scholarship from Nantes University (Ecole doctorale BS) funded by the French ministry MEESR. U.H. received financial support from ITMO Cancer of Aviesan on funds administered by Inserm.

**Institutional Review Board Statement:** Not applicable.
desired components into exosomes has proven challenging at times [283]. In addition to the advantages afforded by standardized liposomes for the delivery of therapeutics, the “exosome” strategy is being challenged by other strategies for the custom development of delivery systems based, for example, on bacteriophage virus-like particles (VLPs) [284] or other biomimetic platforms [285]. Future research on exosomes for vaccine purposes will have to establish a comparison with these other types of nano-platforms, particularly in preclinical studies. Furthermore, when exosomes are injected into a patient, they may compete with their endogenous counterparts, potentially affecting the desired therapeutic effects [282], or interfering with intercellular communication networks. They may also bind to competitive ligands instead of cell receptors [286]. Exosomes harvested from DCs could hold the best vaccine potential, as they naturally express antigen-presentation molecules. This strategy has already proven its relevance in oncology, with DC exosome-based vaccines that have passed both preclinical and clinical phases, demonstrating good tolerance and safety [287,288]. On the downside, the many clinical trials carried out in recent years with exosome-based cancer immunotherapies have not always produced the expected results, prompting further research into the immune mechanisms controlled by exosomes in vivo [289].

Finally, ethical considerations surrounding safety, informed consent, and unpredictable consequences must be addressed. Rigorous testing, transparency in research, and clear patient communication are essential. Balancing innovation with ethical standards is paramount to harness the full potential of exosomes in medicine. The evolution of guidelines to ensure responsible and beneficial applications is strikingly evident.

## 8. Concluding Remarks

The global health crisis caused by SARS-CoV-2 has reinforced the need to diversify vaccine strategies against viral infections. This, in turn, has renewed interest in exosomes as particularly attractive nanocarriers. We therefore set out to review the literature on the biology of exosomes, which mediate signaling between cells and play a key role in both physiological and pathological processes. We pointed out their considerable relevance as potential biomarkers and diagnostic, and therapeutic tools in contemporary medicine. Their role in viral infections is increasingly studied, and we have pointed out that it is often dual, complicating the prospects for their therapeutic usage. However, significant advances in the engineering of these vesicles for the custom loading of proteins or RNAs confirm that they are interesting nano-vectors of new therapeutic molecules. Likewise, exosomes could benefit from the innovative design of vaccines, unveiling novel strategies for viral infection control. The recent demonstration of their efficacy in preclinical models strengthens their use as original platforms for antigen presentation or mRNA vectorization systems. However, uncertainties remain on several aspects such as the choice of exosome-producing cells, engineering methods, standardized production, the safety of administration, and ethical considerations. Nevertheless, this paves the way for the exploration of new approaches to control flavivirus infections, such as DENV or ZIKV, for which vaccine design has become challenging. The transition to clinical trials will, of course, be necessary to validate these approaches and, hopefully, propel exosome-based therapies from bench to bedside.

**Author Contributions:** Conceptualization, D.E.S., A.M., M.K., A.L., U.H., G.L., W.V. and P.K.-T.; Methodology, resources, and writing—original draft preparation, D.E.S., A.M., M.K., A.L., U.H., G.L., W.V. and P.K.-T.; Figure drawings, D.E.S., G.L. and M.K.; Writing—review and editing, D.E.S., A.M. and P.K.-T.; Visualization, P.K.-T. and W.V.; Supervision, P.K.-T.; Funding acquisition, W.V. and P.K.-T. All authors have read and agreed to the published version of the manuscript.

**Funding:** D.E.S. has PhD degree scholarships from Réunion University (Ecole doctorale STS) funded by DIRED/2021-1115 Région Réunion, and M.K. has a PhD degree scholarship from Nantes University (Ecole doctorale BS) funded by the French ministry MEESR. U.H. received financial support from ITMO Cancer of Aviesan on funds administered by Inserm.

**Institutional Review Board Statement:** Not applicable.
**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data sharing is not applicable.

**Acknowledgments:** All figures were created using Biorender.com (accessed on the 1 December 2023).

**Conflicts of Interest:** The authors declare no conflicts of interest.

**Abbreviations**

<table><tr><td>ALIX</td><td>ALG-2-interacting protein X</td></tr><tr><td>APCs</td><td>antigen-presenting cells</td></tr><tr><td>APOBEC3G</td><td>apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G</td></tr><tr><td>BMDCs</td><td>bone marrow-derived dendritic cells</td></tr><tr><td>CCL2</td><td>C-C motif chemokine ligand 2</td></tr><tr><td>cGAS-STING</td><td>cyclic GMP-AMP synthase stimulator of interferon genes</td></tr><tr><td>CHIKV</td><td>Chikungunya virus</td></tr><tr><td>CHMP4</td><td>charged multivesicular body protein 4a</td></tr><tr><td>circRNAs</td><td>circular RNAs</td></tr><tr><td>CMV</td><td>cytomegalovirus</td></tr><tr><td>CTL</td><td>cytotoxic T lymphocyte</td></tr><tr><td>DC</td><td>dendritic cell</td></tr><tr><td>DENV</td><td>Dengue virus</td></tr><tr><td>DUBs</td><td>de-ubiquitylating enzymes</td></tr><tr><td>EBV</td><td>Epstein-Barr virus</td></tr><tr><td>EMT</td><td>epithelial-mesenchymal transition</td></tr><tr><td>ESCRT</td><td>Endosomal Sorting Complex Required for Transport</td></tr><tr><td>EV</td><td>extracellular vesicles</td></tr><tr><td>HBsAg</td><td>hepatitis B antigen</td></tr><tr><td>HBV</td><td>hepatitis B virus</td></tr><tr><td>HCV</td><td>hepatitis C virus</td></tr><tr><td>HGF</td><td>hepatocyte growth factor</td></tr><tr><td>HIV</td><td>human immunodeficiency virus</td></tr><tr><td>HLA-DR</td><td>Human Leukocyte Antigen DR isotype</td></tr><tr><td>HNRNPs</td><td>heterogeneous nuclear ribonucleoproteins</td></tr><tr><td>HNSCC</td><td>Head and Neck Squamous-Cell Carcinoma</td></tr><tr><td>HSP70</td><td>heat shock protein 70</td></tr><tr><td>ICAM-1</td><td>intercellular adhesion molecule 1</td></tr><tr><td>IC50</td><td>half maximal inhibitory concentration</td></tr><tr><td>IFITM3</td><td>interferon-induced transmembrane protein 3</td></tr><tr><td>IFNα</td><td>interferon alpha</td></tr><tr><td>IFNγ</td><td>interferon gamma</td></tr><tr><td>IgG</td><td>immunoglobulin G</td></tr><tr><td>IL-1β</td><td>interleukin-1β</td></tr><tr><td>ILVs</td><td>intraluminal vesicles</td></tr><tr><td>IP-10</td><td>interferon gamma-induced protein</td></tr><tr><td>ISGs</td><td>interferon-stimulated genes</td></tr><tr><td>JEV</td><td>Japanese encephalitis virus</td></tr><tr><td>L1</td><td>non-LTR retrotransposons LINE-1</td></tr><tr><td>LPS</td><td>lipopolysaccharides</td></tr><tr><td>MCP-1</td><td>monocyte chemoattractant protein-1</td></tr><tr><td>MEVs</td><td>multi-epitope vaccines</td></tr><tr><td>MHC</td><td>major histocompatibility complex</td></tr><tr><td>MSCs</td><td>mesenchymal stromal cells</td></tr><tr><td>mo-DCs</td><td>monocyte-derived dendritic cells</td></tr><tr><td>MVBs</td><td>multivesicular bodies</td></tr><tr><td>NS1</td><td>non-structural protein-1</td></tr><tr><td>PRRs</td><td>pattern recognition receptors</td></tr><tr><td>RANTES</td><td>regulated upon activation normal T cell expressed and secreted</td></tr></table>
**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Data sharing is not applicable.

**Acknowledgments:** All figures were created using Biorender.com (accessed on the 1 December 2023).

**Conflicts of Interest:** The authors declare no conflicts of interest.

**Abbreviations**

<table><tr><td>ALIX</td><td>ALG-2-interacting protein X</td></tr><tr><td>APCs</td><td>antigen-presenting cells</td></tr><tr><td>APOBEC3G</td><td>apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G</td></tr><tr><td>BMDCs</td><td>bone marrow-derived dendritic cells</td></tr><tr><td>CCL2</td><td>C-C motif chemokine ligand 2</td></tr><tr><td>cGAS-STING</td><td>cyclic GMP-AMP synthase stimulator of interferon genes</td></tr><tr><td>CHIKV</td><td>Chikungunya virus</td></tr><tr><td>CHMP4</td><td>charged multivesicular body protein 4a</td></tr><tr><td>circRNAs</td><td>circular RNAs</td></tr><tr><td>CMV</td><td>cytomegalovirus</td></tr><tr><td>CTL</td><td>cytotoxic T lymphocyte</td></tr><tr><td>DC</td><td>dendritic cell</td></tr><tr><td>DENV</td><td>Dengue virus</td></tr><tr><td>DUBs</td><td>de-ubiquitylating enzymes</td></tr><tr><td>EBV</td><td>Epstein-Barr virus</td></tr><tr><td>EMT</td><td>epithelial-mesenchymal transition</td></tr><tr><td>ESCRT</td><td>Endosomal Sorting Complex Required for Transport</td></tr><tr><td>EV</td><td>extracellular vesicles</td></tr><tr><td>HBsAg</td><td>hepatitis B antigen</td></tr><tr><td>HBV</td><td>hepatitis B virus</td></tr><tr><td>HCV</td><td>hepatitis C virus</td></tr><tr><td>HGF</td><td>hepatocyte growth factor</td></tr><tr><td>HIV</td><td>human immunodeficiency virus</td></tr><tr><td>HLA-DR</td><td>Human Leukocyte Antigen DR isotype</td></tr><tr><td>HNRNPs</td><td>heterogeneous nuclear ribonucleoproteins</td></tr><tr><td>HNSCC</td><td>Head and Neck Squamous-Cell Carcinoma</td></tr><tr><td>HSP70</td><td>heat shock protein 70</td></tr><tr><td>ICAM-1</td><td>intercellular adhesion molecule 1</td></tr><tr><td>IC50</td><td>half maximal inhibitory concentration</td></tr><tr><td>IFITM3</td><td>interferon-induced transmembrane protein 3</td></tr><tr><td>IFNα</td><td>interferon alpha</td></tr><tr><td>IFNγ</td><td>interferon gamma</td></tr><tr><td>IgG</td><td>immunoglobulin G</td></tr><tr><td>IL-1β</td><td>interleukin-1β</td></tr><tr><td>ILVs</td><td>intraluminal vesicles</td></tr><tr><td>IP-10</td><td>interferon gamma-induced protein</td></tr><tr><td>ISGs</td><td>interferon-stimulated genes</td></tr><tr><td>JEV</td><td>Japanese encephalitis virus</td></tr><tr><td>L1</td><td>non-LTR retrotransposons LINE-1</td></tr><tr><td>LPS</td><td>lipopolysaccharides</td></tr><tr><td>MCP-1</td><td>monocyte chemoattractant protein-1</td></tr><tr><td>MEVs</td><td>multi-epitope vaccines</td></tr><tr><td>MHC</td><td>major histocompatibility complex</td></tr><tr><td>MSCs</td><td>mesenchymal stromal cells</td></tr><tr><td>mo-DCs</td><td>monocyte-derived dendritic cells</td></tr><tr><td>MVBs</td><td>multivesicular bodies</td></tr><tr><td>NS1</td><td>non-structural protein-1</td></tr><tr><td>PRRs</td><td>pattern recognition receptors</td></tr><tr><td>RANTES</td><td>regulated upon activation normal T cell expressed and secreted</td></tr></table>
<table><tr><td>RBD</td><td>receptor-binding domain</td></tr><tr><td>RLRs</td><td>RIG-I like receptors</td></tr><tr><td>RSV</td><td>respiratory syncytial virus</td></tr><tr><td>SIgA</td><td>secretory IgA</td></tr><tr><td>SNARE</td><td>soluble NSF attachment protein receptor</td></tr><tr><td>SARS-CoV-2</td><td>Severe Acute Respiratory Syndrome Coronavirus 2</td></tr><tr><td>STING</td><td>stimulator of interferon genes</td></tr><tr><td>TAR</td><td>trans-activation response element</td></tr><tr><td>TBEV</td><td>tick-borne encephalitis virus</td></tr><tr><td>TGFβ</td><td>Tumor Growth Factor β</td></tr><tr><td>TIM4</td><td>T-cell immunoglobulin- and mucin-domain-containing molecule 4</td></tr><tr><td>TNFα</td><td>Tumor Necrosis Factor α</td></tr><tr><td>TSG101</td><td>tumor susceptibility gene 101</td></tr><tr><td>VLPs</td><td>virus-like particles</td></tr><tr><td>VSV-G</td><td>vesicular stomatitis virus glycoprotein</td></tr><tr><td>WNV</td><td>West Nile virus</td></tr><tr><td>ZIKV</td><td>Zika virus</td></tr></table>

## References

1. Théry, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, biogenesis and function. *Nat. Rev. Immunol.* **2002**, *2*, 569–579. [CrossRef]

2. Théry, C.; Duban, L.; Segura, E.; Véron, P.; Lantz, O.; Amigorena, S. Indirect activation of naïve CD4⁺ T cells by dendritic cell-derived exosomes. *Nat. Immunol.* **2002**, *3*, 1156–1162. [CrossRef]

3. Lindenbergh, M.F.S.; Stoorvogel, W. Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells. *Annu. Rev. Immunol.* **2018**, *36*, 435–459. [CrossRef] [PubMed]

4. Raposo, G.; Nijman, H.W.; Stoorvogel, W.; Liejendekker, R.; Harding, C.V.; Melief, C.J.; Geuze, H.J. B lymphocytes secrete antigen-presenting vesicles. *J. Exp. Med.* **1996**, *183*, 1161–1172. [CrossRef] [PubMed]

5. Marar, C.; Starich, B.; Wirtz, D. Extracellular vesicles in immunomodulation and tumor progression. *Nat. Immunol.* **2021**, *22*, 560–570. [CrossRef] [PubMed]

6. Coumans, F.A.W.; Brisson, A.R.; Buzas, E.I.; Dignat-George, F.; Drees, E.E.E.; El-Andaloussi, S.; Emanueli, C.; Gasecka, A.; Hendrix, A.; Hill, A.F.; et al. Methodological Guidelines to Study Extracellular Vesicles. *Circ. Res.* **2017**, *120*, 1632–1648. [CrossRef] [PubMed]

7. Fan, S.; Poetsch, A. Proteomic Research of Extracellular Vesicles in Clinical Biofluid. *Proteomes* **2023**, *11*, 18. [CrossRef] [PubMed]

8. Zhu, J.; Wu, F.; Li, C.; Mao, J.; Wang, Y.; Zhou, X.; Xie, H.; Wen, C. Application of Single Extracellular Vesicle Analysis Techniques. *Int. J. Nanomed.* **2023**, *18*, 5365–5376. [CrossRef] [PubMed]

9. Witwer, K.W.; Goberdhan, D.C.; O'Driscoll, L.; Théry, C.; Welsh, J.A.; Blenkiron, C.; Buzás, E.I.; Di Vizio, D.; Erdbrügger, U.; Falcón-Pérez, J.M.; et al. Updating MISEV: Evolving the minimal requirements for studies of extracellular vesicles. *J. Extracell. Vesicles* **2021**, *10*, e12182. [CrossRef] [PubMed]

10. Bazzan, E.; Tinè, M.; Casara, A.; Biondini, D.; Semenzato, U.; Cocconcelli, E.; Balestro, E.; Damin, M.; Radu, C.M.; Turato, G.; et al. Critical Review of the Evolution of Extracellular Vesicles' Knowledge: From 1946 to Today. *Int. J. Mol. Sci.* **2021**, *22*, 6417. [CrossRef]

11. Hendrix, A.; Lippens, L.; Pinheiro, C.; Théry, C.; Martin-Jaular, L.; Lötvall, J.; Lässer, C.; Hill, A.F.; Witwer, K.W. Extracellular vesicle analysis. *Nat. Rev. Methods Primer* **2023**, *3*, 56. [CrossRef]

12. Van Niel, G.; D'Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. *Nat. Rev. Mol. Cell Biol.* **2018**, *19*, 213–228. [CrossRef]

13. Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. *Cells* **2019**, *8*, 727. [CrossRef]

14. Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. *Science* **2020**, *367*, eaau6977. [CrossRef] [PubMed]

15. Cappe, B.; Vandenabeele, P.; Riquet, F.B. A guide to the expanding field of extracellular vesicles and their release in regulated cell death programs. *FEBS J.* **2023; early view.** [CrossRef] [PubMed]

16. Deatherage, B.L.; Cookson, B.T. Membrane vesicle release in bacteria, eukaryotes, and archaea: A conserved yet underappreciated aspect of microbial life. *Infect. Immun.* **2012**, *80*, 1948–1957. [CrossRef] [PubMed]

17. De la Torre Gomez, C.; Goreham, R.V.; Serra, J.J.B.; Nann, T.; Kussmann, M. "Exosomics"—A Review of Biophysics, Biology and Biochemistry of Exosomes with a Focus on Human Breast Milk. *Front. Genet.* **2018**, *9*, 92. [CrossRef] [PubMed]

18. Yokoi, A.; Ochiya, T. Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology. *Semin. Cancer Biol.* **2021**, *74*, 79–91. [CrossRef]

19. Izadpanah, M.; Seddigh, A.; Barough, S.E.; Fazeli, S.A.S.; Ai, J. Potential of Extracellular Vesicles in Neurodegenerative Diseases: Diagnostic and Therapeutic Indications. *J. Mol. Neurosci.* **MN 2018**, *66*, 172–179. [CrossRef] [PubMed]
<table><tr><td>RBD</td><td>receptor-binding domain</td></tr><tr><td>RLRs</td><td>RIG-I like receptors</td></tr><tr><td>RSV</td><td>respiratory syncytial virus</td></tr><tr><td>SIgA</td><td>secretory IgA</td></tr><tr><td>SNARE</td><td>soluble NSF attachment protein receptor</td></tr><tr><td>SARS-CoV-2</td><td>Severe Acute Respiratory Syndrome Coronavirus 2</td></tr><tr><td>STING</td><td>stimulator of interferon genes</td></tr><tr><td>TAR</td><td>trans-activation response element</td></tr><tr><td>TBEV</td><td>tick-borne encephalitis virus</td></tr><tr><td>TGFβ</td><td>Tumor Growth Factor β</td></tr><tr><td>TIM4</td><td>T-cell immunoglobulin- and mucin-domain-containing molecule 4</td></tr><tr><td>TNFα</td><td>Tumor Necrosis Factor α</td></tr><tr><td>TSG101</td><td>tumor susceptibility gene 101</td></tr><tr><td>VLPs</td><td>virus-like particles</td></tr><tr><td>VSV-G</td><td>vesicular stomatitis virus glycoprotein</td></tr><tr><td>WNV</td><td>West Nile virus</td></tr><tr><td>ZIKV</td><td>Zika virus</td></tr></table>

## References

1. Théry, C.; Zitvogel, L.; Amigorena, S. Exosomes: Composition, biogenesis and function. *Nat. Rev. Immunol.* **2002**, *2*, 569–579. [CrossRef]

2. Théry, C.; Duban, L.; Segura, E.; Véron, P.; Lantz, O.; Amigorena, S. Indirect activation of naïve CD4⁺ T cells by dendritic cell-derived exosomes. *Nat. Immunol.* **2002**, *3*, 1156–1162. [CrossRef]

3. Lindenbergh, M.F.S.; Stoorvogel, W. Antigen Presentation by Extracellular Vesicles from Professional Antigen-Presenting Cells. *Annu. Rev. Immunol.* **2018**, *36*, 435–459. [CrossRef] [PubMed]

4. Raposo, G.; Nijman, H.W.; Stoorvogel, W.; Liejendekker, R.; Harding, C.V.; Melief, C.J.; Geuze, H.J. B lymphocytes secrete antigen-presenting vesicles. *J. Exp. Med.* **1996**, *183*, 1161–1172. [CrossRef] [PubMed]

5. Marar, C.; Starich, B.; Wirtz, D. Extracellular vesicles in immunomodulation and tumor progression. *Nat. Immunol.* **2021**, *22*, 560–570. [CrossRef] [PubMed]

6. Coumans, F.A.W.; Brisson, A.R.; Buzas, E.I.; Dignat-George, F.; Drees, E.E.E.; El-Andaloussi, S.; Emanueli, C.; Gasecka, A.; Hendrix, A.; Hill, A.F.; et al. Methodological Guidelines to Study Extracellular Vesicles. *Circ. Res.* **2017**, *120*, 1632–1648. [CrossRef] [PubMed]

7. Fan, S.; Poetsch, A. Proteomic Research of Extracellular Vesicles in Clinical Biofluid. *Proteomes* **2023**, *11*, 18. [CrossRef] [PubMed]

8. Zhu, J.; Wu, F.; Li, C.; Mao, J.; Wang, Y.; Zhou, X.; Xie, H.; Wen, C. Application of Single Extracellular Vesicle Analysis Techniques. *Int. J. Nanomed.* **2023**, *18*, 5365–5376. [CrossRef] [PubMed]

9. Witwer, K.W.; Goberdhan, D.C.; O'Driscoll, L.; Théry, C.; Welsh, J.A.; Blenkiron, C.; Buzás, E.I.; Di Vizio, D.; Erdbrügger, U.; Falcón-Pérez, J.M.; et al. Updating MISEV: Evolving the minimal requirements for studies of extracellular vesicles. *J. Extracell. Vesicles* **2021**, *10*, e12182. [CrossRef] [PubMed]

10. Bazzan, E.; Tinè, M.; Casara, A.; Biondini, D.; Semenzato, U.; Cocconcelli, E.; Balestro, E.; Damin, M.; Radu, C.M.; Turato, G.; et al. Critical Review of the Evolution of Extracellular Vesicles' Knowledge: From 1946 to Today. *Int. J. Mol. Sci.* **2021**, *22*, 6417. [CrossRef]

11. Hendrix, A.; Lippens, L.; Pinheiro, C.; Théry, C.; Martin-Jaular, L.; Lötvall, J.; Lässer, C.; Hill, A.F.; Witwer, K.W. Extracellular vesicle analysis. *Nat. Rev. Methods Primer* **2023**, *3*, 56. [CrossRef]

12. Van Niel, G.; D'Angelo, G.; Raposo, G. Shedding light on the cell biology of extracellular vesicles. *Nat. Rev. Mol. Cell Biol.* **2018**, *19*, 213–228. [CrossRef]

13. Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. *Cells* **2019**, *8*, 727. [CrossRef]

14. Kalluri, R.; LeBleu, V.S. The biology, function, and biomedical applications of exosomes. *Science* **2020**, *367*, eaau6977. [CrossRef] [PubMed]

15. Cappe, B.; Vandenabeele, P.; Riquet, F.B. A guide to the expanding field of extracellular vesicles and their release in regulated cell death programs. *FEBS J.* **2023; early view.** [CrossRef] [PubMed]

16. Deatherage, B.L.; Cookson, B.T. Membrane vesicle release in bacteria, eukaryotes, and archaea: A conserved yet underappreciated aspect of microbial life. *Infect. Immun.* **2012**, *80*, 1948–1957. [CrossRef] [PubMed]

17. De la Torre Gomez, C.; Goreham, R.V.; Serra, J.J.B.; Nann, T.; Kussmann, M. "Exosomics"—A Review of Biophysics, Biology and Biochemistry of Exosomes with a Focus on Human Breast Milk. *Front. Genet.* **2018**, *9*, 92. [CrossRef] [PubMed]

18. Yokoi, A.; Ochiya, T. Exosomes and extracellular vesicles: Rethinking the essential values in cancer biology. *Semin. Cancer Biol.* **2021**, *74*, 79–91. [CrossRef]

19. Izadpanah, M.; Seddigh, A.; Barough, S.E.; Fazeli, S.A.S.; Ai, J. Potential of Extracellular Vesicles in Neurodegenerative Diseases: Diagnostic and Therapeutic Indications. *J. Mol. Neurosci.* **MN 2018**, *66*, 172–179. [CrossRef] [PubMed]
20. Petroni, D.; Fabbri, C.; Babboni, S.; Menichetti, L.; Basta, G.; Del Turco, S. Extracellular Vesicles and Intercellular Communication: Challenges for In Vivo Molecular Imaging and Tracking. *Pharmaceutics* **2023**, *15*, 1639. [CrossRef]

21. Théry, C. Exosomes: Secreted vesicles and intercellular communications. *F1000 Biol. Rep.* **2011**, *3*, 15. [CrossRef]

22. Meldolesi, J. Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes. *Front. Cell Dev. Biol.* **2022**, *10*, 877344. [CrossRef]

23. van Niel, G.; Carter, D.R.F.; Clayton, A.; Lambert, D.W.; Raposo, G.; Vader, P. Challenges and directions in studying cell-cell communication by extracellular vesicles. *Nat. Rev. Mol. Cell Biol.* **2022**, *23*, 369–382. [CrossRef]

24. Mori, T.; Giovannelli, L.; Bilia, A.R.; Margheri, F. Exosomes: Potential Next-Generation Nanocarriers for the Therapy of Inflammatory Diseases. *Pharmaceutics* **2023**, *15*, 2276. [CrossRef] [PubMed]

25. Krylova, S.V.; Feng, D. The Machinery of Exosomes: Biogenesis, Release, and Uptake. *Int. J. Mol. Sci.* **2023**, *24*, 1337. [CrossRef] [PubMed]

26. Gruenberg, J. Life in the lumen: The multivesicular endosome. *Traffic* **2020**, *21*, 76–93. [CrossRef] [PubMed]

27. Naslavsky, N.; Caplan, S. The enigmatic endosome—Sorting the ins and outs of endocytic trafficking. *J. Cell Sci.* **2018**, *131*, jcs216499. [CrossRef] [PubMed]

28. Norris, A.; Grant, B.D. Endosomal microdomains: Formation and function. *Curr. Opin. Cell Biol.* **2020**, *65*, 86–95. [CrossRef] [PubMed]

29. Solinger, J.A.; Spang, A. Sorting of cargo in the tubular endosomal network. *BioEssays* **2022**, *44*, 2200158. [CrossRef] [PubMed]

30. Sigismund, S.; Lanzetti, L.; Scita, G.; Di Fiore, P.P. Endocytosis in the context-dependent regulation of individual and collective cell properties. *Nat. Rev. Mol. Cell Biol.* **2021**, *22*, 625–643. [CrossRef]

31. Pfitzner, A.-K.; Zivkovic, H.; Bernat-Silvestre, C.; West, M.; Peltier, T.; Humbert, F.; Odorizzi, G.; Roux, A. Vps60 initiates alternative ESCRT-III filaments. *J. Cell Biol.* **2023**, *222*, e202206028. [CrossRef]

32. Colombo, M.; Raposo, G.; Théry, C. Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. *Annu. Rev. Cell Dev. Biol.* **2014**, *30*, 255–289. [CrossRef]

33. Kuchitsu, Y.; Taguchi, T. Lysosomal microautophagy: An emerging dimension in mammalian autophagy. *Trends Cell Biol.* **2023**, S0962892423002386. [CrossRef]

34. Huotari, J.; Helenius, A. Endosome maturation: Endosome maturation. *EMBO J.* **2011**, *30*, 3481–3500. [CrossRef] [PubMed]

35. Carlton, J.G.; Baum, B. Roles of ESCRT-III polymers in cell division across the tree of life. *Curr. Opin. Cell Biol.* **2023**, *85*, 102274. [CrossRef] [PubMed]

36. Schöneberg, J.; Lee, I.-H.; Iwasa, J.H.; Hurley, J.H. Reverse-topology membrane scission by the ESCRT proteins. *Nat. Rev. Mol. Cell Biol.* **2017**, *18*, 5–17. [CrossRef]

37. Rivera-Cuevas, Y.; Carruthers, V.B. The multifaceted interactions between pathogens and host ESCRT machinery. *PLoS Pathog.* **2023**, *19*, e1011344. [CrossRef]

38. Jin, X.; Xia, T.; Luo, S.; Zhang, Y.; Xia, Y.; Yin, H. Exosomal lipid PI4P regulates small extracellular vesicle secretion by modulating intraluminal vesicle formation. *J. Extracell. Vesicles* **2023**, *12*, 12319. [CrossRef] [PubMed]

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21. Théry, C. Exosomes: Secreted vesicles and intercellular communications. *F1000 Biol. Rep.* **2011**, *3*, 15. [CrossRef]

22. Meldolesi, J. Unconventional Protein Secretion Dependent on Two Extracellular Vesicles: Exosomes and Ectosomes. *Front. Cell Dev. Biol.* **2022**, *10*, 877344. [CrossRef]

23. van Niel, G.; Carter, D.R.F.; Clayton, A.; Lambert, D.W.; Raposo, G.; Vader, P. Challenges and directions in studying cell-cell communication by extracellular vesicles. *Nat. Rev. Mol. Cell Biol.* **2022**, *23*, 369–382. [CrossRef]

24. Mori, T.; Giovannelli, L.; Bilia, A.R.; Margheri, F. Exosomes: Potential Next-Generation Nanocarriers for the Therapy of Inflammatory Diseases. *Pharmaceutics* **2023**, *15*, 2276. [CrossRef] [PubMed]

25. Krylova, S.V.; Feng, D. The Machinery of Exosomes: Biogenesis, Release, and Uptake. *Int. J. Mol. Sci.* **2023**, *24*, 1337. [CrossRef] [PubMed]

26. Gruenberg, J. Life in the lumen: The multivesicular endosome. *Traffic* **2020**, *21*, 76–93. [CrossRef] [PubMed]

27. Naslavsky, N.; Caplan, S. The enigmatic endosome—Sorting the ins and outs of endocytic trafficking. *J. Cell Sci.* **2018**, *131*, jcs216499. [CrossRef] [PubMed]

28. Norris, A.; Grant, B.D. Endosomal microdomains: Formation and function. *Curr. Opin. Cell Biol.* **2020**, *65*, 86–95. [CrossRef] [PubMed]

29. Solinger, J.A.; Spang, A. Sorting of cargo in the tubular endosomal network. *BioEssays* **2022**, *44*, 2200158. [CrossRef] [PubMed]

30. Sigismund, S.; Lanzetti, L.; Scita, G.; Di Fiore, P.P. Endocytosis in the context-dependent regulation of individual and collective cell properties. *Nat. Rev. Mol. Cell Biol.* **2021**, *22*, 625–643. [CrossRef]

31. Pfitzner, A.-K.; Zivkovic, H.; Bernat-Silvestre, C.; West, M.; Peltier, T.; Humbert, F.; Odorizzi, G.; Roux, A. Vps60 initiates alternative ESCRT-III filaments. *J. Cell Biol.* **2023**, *222*, e202206028. [CrossRef]

32. Colombo, M.; Raposo, G.; Théry, C. Biogenesis, Secretion, and Intercellular Interactions of Exosomes and Other Extracellular Vesicles. *Annu. Rev. Cell Dev. Biol.* **2014**, *30*, 255–289. [CrossRef]

33. Kuchitsu, Y.; Taguchi, T. Lysosomal microautophagy: An emerging dimension in mammalian autophagy. *Trends Cell Biol.* **2023**, S0962892423002386. [CrossRef]

34. Huotari, J.; Helenius, A. Endosome maturation: Endosome maturation. *EMBO J.* **2011**, *30*, 3481–3500. [CrossRef] [PubMed]

35. Carlton, J.G.; Baum, B. Roles of ESCRT-III polymers in cell division across the tree of life. *Curr. Opin. Cell Biol.* **2023**, *85*, 102274. [CrossRef] [PubMed]

36. Schöneberg, J.; Lee, I.-H.; Iwasa, J.H.; Hurley, J.H. Reverse-topology membrane scission by the ESCRT proteins. *Nat. Rev. Mol. Cell Biol.* **2017**, *18*, 5–17. [CrossRef]

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212. Xi, Y.; Ju, R.; Wang, Y. Mesenchymal Stem Cell-Derived Extracellular Vesicles for the Treatment of Bronchopulmonary Dysplasia. *Front. Pediatr.* **2022**, *10*, 852034. [CrossRef] [PubMed]

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214. Santos, C.C.D.; Lopes-Pacheco, M.; English, K.; Enes, S.R.; Krasnodembskaya, A.; Rocco, P.R.M. The MSC-EV-microRNAome: A Perspective on Therapeutic Mechanisms of Action in Sepsis and ARDS. *Cells* **2024**, *13*, 122. [CrossRef] [PubMed]

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216. Sun, X.-H.; Wang, X.; Zhang, Y.; Hui, J. Exosomes of bone-marrow stromal cells inhibit cardiomyocyte apoptosis under ischemic and hypoxic conditions via miR-486-5p targeting the PTEN/PI3K/AKT signaling pathway. *Thromb. Res.* **2019**, *177*, 23–32. [CrossRef]

217. Yue, R.; Lu, S.; Luo, Y.; Zeng, J.; Liang, H.; Qin, D.; Wang, X.; Wang, T.; Pu, J.; Hu, H. Mesenchymal stem cell-derived exosomal microRNA-182-5p alleviates myocardial ischemia/reperfusion injury by targeting GSDMD in mice. *Cell Death Discov.* **2022**, *8*, 202. [CrossRef]

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219. Kamm, D.R.; McCommis, K.S. Hepatic stellate cells in physiology and pathology. *J. Physiol.* **2022**, *600*, 1825–1837. [CrossRef]

220. Rong, X.; Liu, J.; Yao, X.; Jiang, T.; Wang, Y.; Xie, F. Human bone marrow mesenchymal stem cells-derived exosomes alleviate liver fibrosis through the Wnt/β-catenin pathway. *Stem Cell Res. Ther.* **2019**, *10*, 98. [CrossRef]

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233. Tian, Y.; Li, S.; Song, J.; Ji, T.; Zhu, M.; Anderson, G.J.; Wei, J.; Nie, G. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. *Biomaterials* **2014**, *35*, 2383–2390. [CrossRef] [PubMed]

234. Haney, M.J.; Zhao, Y.; Harrison, E.B.; Mahajan, V.; Ahmed, S.; He, Z.; Suresh, P.; Hingtgen, S.D.; Klyachko, N.L.; Mosley, R.L.; et al. Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases. *PLoS ONE* **2013**, *8*, e61852. [CrossRef]

235. Zhao, Y.; Haney, M.J.; Gupta, R.; Bohnsack, J.P.; He, Z.; Kabanov, A.V.; Batrakova, E.V. GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson's Disease Mouse Model. *PLoS ONE* **2014**, *9*, e106867. [CrossRef]

236. Liang, G.; Zhu, Y.; Ali, D.J.; Tian, T.; Xu, H.; Si, K.; Sun, B.; Chen, B.; Xiao, Z. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. *J. Nanobiotechnol.* **2020**, *18*, 10. [CrossRef]

237. Koh, H.B.; Kim, H.J.; Kang, S.-W.; Yoo, T.-H. Exosome-Based Drug Delivery: Translation from Bench to Clinic. *Pharmaceutics* **2023**, *15*, 2042. [CrossRef]

238. Marschall, A.L.J. Targeting the Inside of Cells with Biologicals: Chemicals as a Delivery Strategy. *BioDrugs* **2021**, *35*, 643–671. [CrossRef]

239. Herrmann, I.K.; Wood, M.J.A.; Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. *Nat. Nanotechnol.* **2021**, *16*, 748–759. [CrossRef]

240. Sercombe, L.; Veerati, T.; Moheimani, F.; Wu, S.Y.; Sood, A.K.; Hua, S. Advances and Challenges of Liposome Assisted Drug Delivery. *Front. Pharmacol.* **2015**, *6*, 286. [CrossRef] [PubMed]

241. Murphy, D.E.; De Jong, O.G.; Evers, M.J.W.; Nurazizah, M.; Schiffelers, R.M.; Vader, P. Natural or Synthetic RNA Delivery: A Stoichiometric Comparison of Extracellular Vesicles and Synthetic Nanoparticles. *Nano Lett.* **2021**, *21*, 1888–1895. [CrossRef]

242. Hodge, A.L.; Baxter, A.A.; Poon, I.K.H. Gift bags from the sentinel cells of the immune system: The diverse role of dendritic cell-derived extracellular vesicles. *J. Leukoc. Biol.* **2022**, *111*, 903–920. [CrossRef]

243. Segura, E.; Amigorena, S.; Théry, C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. *Blood Cells. Mol. Dis.* **2005**, *35*, 89–93. [CrossRef] [PubMed]

244. Lindenbergh, M.F.S.; Koerhuis, D.G.J.; Borg, E.G.F.; Veld, E.M.T.; Driedonks, T.A.P.; Wubbolts, R.; Stoorvogel, W.; Boes, M. Bystander T-Cells Support Clonal T-Cell Activation by Controlling the Release of Dendritic Cell-Derived Immune-Stimulatory Extracellular Vesicles. *Front. Immunol.* **2019**, *10*, 448. [CrossRef] [PubMed]

245. Lindenbergh, M.F.S.; Wubbolts, R.; Borg, E.G.F.; Van 'T Veld, E.M.; Boes, M.; Stoorvogel, W. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. *J. Extracell. Vesicles* **2020**, *9*, 1798606. [CrossRef] [PubMed]

246. Montecalvo, A.; Shufesky, W.J.; Stolz, D.B.; Sullivan, M.G.; Wang, Z.; DiVito, S.J.; Papworth, G.D.; Watkins, S.C.; Robbins, P.D.; Larregina, A.T.; et al. Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition. *J. Immunol.* **2008**, *180*, 3081–3090. [CrossRef]

247. Matsuzaka, Y.; Yashiro, R. Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation. *Vaccines* **2022**, *10*, 1691. [CrossRef] [PubMed]

248. Reyes-Ruiz, J.M.; Osuna-Ramos, J.F.; De Jesús-González, L.A.; Palacios-Rápalo, S.N.; Cordero-Rivera, C.D.; Farfan-Morales, C.N.; Hurtado-Monzón, A.M.; Gallardo-Flores, C.E.; Alcaraz-Estrada, S.L.; Salas-Benito, J.S.; et al. The Regulation of Flavivirus Infection by Hijacking Exosome-Mediated Cell-Cell Communication: New Insights on Virus-Host Interactions. *Viruses* **2020**, *12*, 765. [CrossRef] [PubMed]

249. Anderson, M.R.; Pleet, M.L.; Enose-Akahata, Y.; Erickson, J.; Monaco, M.C.; Akpamagbo, Y.; Velluci, A.; Tanaka, Y.; Azodi, S.; Lepene, B.; et al. Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: Functional role of exosomes. *Clin. Transl. Med.* **2018**, *7*, e24. [CrossRef] [PubMed]

250. Pesce, E.; Manfrini, N.; Cordiglieri, C.; Santi, S.; Bandera, A.; Gobbini, A.; Gruarin, P.; Favalli, A.; Bombaci, M.; Cuomo, A.; et al. Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response. *Front. Immunol.* **2022**, *12*, 785941. [CrossRef]
226. Wan, Z.; Zhao, L.; Lu, F.; Gao, X.; Dong, Y.; Zhao, Y.; Wei, M.; Yang, G.; Xing, C.; Liu, L. Mononuclear phagocyte system blockade improves therapeutic exosome delivery to the myocardium. *Theranostics* **2020**, *10*, 218–230. [CrossRef] [PubMed]

227. Lu, Y.; Yang, Y.; Zhu, G.; Zeng, H.; Fan, Y.; Guo, F.; Xu, D.; Wang, B.; Chen, D.; Ge, G. Emerging Pharmacotherapeutic Strategies to Overcome Undruggable Proteins in Cancer. *Int. J. Biol. Sci.* **2023**, *19*, 3360–3382. [CrossRef] [PubMed]

228. Hood, J.L. Post isolation modification of exosomes for nanomedicine applications. *Nanomedicine* **2016**, *11*, 1745–1756. [CrossRef]

229. Bai, J.; Wei, X.; Zhang, X.; Wu, C.; Wang, Z.; Chen, M.; Wang, J. Microfluidic strategies for the isolation and profiling of exosomes. *TrAC Trends Anal. Chem.* **2023**, *158*, 116834. [CrossRef]

230. Kalani, A.; Chaturvedi, P.; Kamat, P.K.; Maldonado, C.; Bauer, P.; Joshua, I.G.; Tyagi, S.C.; Tyagi, N. Curcumin-loaded embryonic stem cell exosomes restored neurovascular unit following ischemia-reperfusion injury. *Int. J. Biochem. Cell Biol.* **2016**, *79*, 360–369. [CrossRef]

231. Li, D.; Zhang, C.; Gao, Z.; Xia, N.; Wu, C.; Liu, C.; Tian, H.; Mei, X. Curcumin-Loaded Macrophage-Derived Exosomes Effectively Improve Wound Healing. *Mol. Pharm.* **2023**, *20*, 4453–4467. [CrossRef]

232. Sadeghi, S.; Tehrani, F.R.; Tahmasebi, S.; Shafiee, A.; Hashemi, S.M. Exosome engineering in cell therapy and drug delivery. *Inflammopharmacology* **2023**, *31*, 145–169. [CrossRef] [PubMed]

233. Tian, Y.; Li, S.; Song, J.; Ji, T.; Zhu, M.; Anderson, G.J.; Wei, J.; Nie, G. A doxorubicin delivery platform using engineered natural membrane vesicle exosomes for targeted tumor therapy. *Biomaterials* **2014**, *35*, 2383–2390. [CrossRef] [PubMed]

234. Haney, M.J.; Zhao, Y.; Harrison, E.B.; Mahajan, V.; Ahmed, S.; He, Z.; Suresh, P.; Hingtgen, S.D.; Klyachko, N.L.; Mosley, R.L.; et al. Specific Transfection of Inflamed Brain by Macrophages: A New Therapeutic Strategy for Neurodegenerative Diseases. *PLoS ONE* **2013**, *8*, e61852. [CrossRef]

235. Zhao, Y.; Haney, M.J.; Gupta, R.; Bohnsack, J.P.; He, Z.; Kabanov, A.V.; Batrakova, E.V. GDNF-Transfected Macrophages Produce Potent Neuroprotective Effects in Parkinson's Disease Mouse Model. *PLoS ONE* **2014**, *9*, e106867. [CrossRef]

236. Liang, G.; Zhu, Y.; Ali, D.J.; Tian, T.; Xu, H.; Si, K.; Sun, B.; Chen, B.; Xiao, Z. Engineered exosomes for targeted co-delivery of miR-21 inhibitor and chemotherapeutics to reverse drug resistance in colon cancer. *J. Nanobiotechnol.* **2020**, *18*, 10. [CrossRef]

237. Koh, H.B.; Kim, H.J.; Kang, S.-W.; Yoo, T.-H. Exosome-Based Drug Delivery: Translation from Bench to Clinic. *Pharmaceutics* **2023**, *15*, 2042. [CrossRef]

238. Marschall, A.L.J. Targeting the Inside of Cells with Biologicals: Chemicals as a Delivery Strategy. *BioDrugs* **2021**, *35*, 643–671. [CrossRef]

239. Herrmann, I.K.; Wood, M.J.A.; Fuhrmann, G. Extracellular vesicles as a next-generation drug delivery platform. *Nat. Nanotechnol.* **2021**, *16*, 748–759. [CrossRef]

240. Sercombe, L.; Veerati, T.; Moheimani, F.; Wu, S.Y.; Sood, A.K.; Hua, S. Advances and Challenges of Liposome Assisted Drug Delivery. *Front. Pharmacol.* **2015**, *6*, 286. [CrossRef] [PubMed]

241. Murphy, D.E.; De Jong, O.G.; Evers, M.J.W.; Nurazizah, M.; Schiffelers, R.M.; Vader, P. Natural or Synthetic RNA Delivery: A Stoichiometric Comparison of Extracellular Vesicles and Synthetic Nanoparticles. *Nano Lett.* **2021**, *21*, 1888–1895. [CrossRef]

242. Hodge, A.L.; Baxter, A.A.; Poon, I.K.H. Gift bags from the sentinel cells of the immune system: The diverse role of dendritic cell-derived extracellular vesicles. *J. Leukoc. Biol.* **2022**, *111*, 903–920. [CrossRef]

243. Segura, E.; Amigorena, S.; Théry, C. Mature dendritic cells secrete exosomes with strong ability to induce antigen-specific effector immune responses. *Blood Cells. Mol. Dis.* **2005**, *35*, 89–93. [CrossRef] [PubMed]

244. Lindenbergh, M.F.S.; Koerhuis, D.G.J.; Borg, E.G.F.; Veld, E.M.T.; Driedonks, T.A.P.; Wubbolts, R.; Stoorvogel, W.; Boes, M. Bystander T-Cells Support Clonal T-Cell Activation by Controlling the Release of Dendritic Cell-Derived Immune-Stimulatory Extracellular Vesicles. *Front. Immunol.* **2019**, *10*, 448. [CrossRef] [PubMed]

245. Lindenbergh, M.F.S.; Wubbolts, R.; Borg, E.G.F.; Van 'T Veld, E.M.; Boes, M.; Stoorvogel, W. Dendritic cells release exosomes together with phagocytosed pathogen; potential implications for the role of exosomes in antigen presentation. *J. Extracell. Vesicles* **2020**, *9*, 1798606. [CrossRef] [PubMed]

246. Montecalvo, A.; Shufesky, W.J.; Stolz, D.B.; Sullivan, M.G.; Wang, Z.; DiVito, S.J.; Papworth, G.D.; Watkins, S.C.; Robbins, P.D.; Larregina, A.T.; et al. Exosomes As a Short-Range Mechanism to Spread Alloantigen between Dendritic Cells during T Cell Allorecognition. *J. Immunol.* **2008**, *180*, 3081–3090. [CrossRef]

247. Matsuzaka, Y.; Yashiro, R. Regulation of Extracellular Vesicle-Mediated Immune Responses against Antigen-Specific Presentation. *Vaccines* **2022**, *10*, 1691. [CrossRef] [PubMed]

248. Reyes-Ruiz, J.M.; Osuna-Ramos, J.F.; De Jesús-González, L.A.; Palacios-Rápalo, S.N.; Cordero-Rivera, C.D.; Farfan-Morales, C.N.; Hurtado-Monzón, A.M.; Gallardo-Flores, C.E.; Alcaraz-Estrada, S.L.; Salas-Benito, J.S.; et al. The Regulation of Flavivirus Infection by Hijacking Exosome-Mediated Cell-Cell Communication: New Insights on Virus-Host Interactions. *Viruses* **2020**, *12*, 765. [CrossRef] [PubMed]

249. Anderson, M.R.; Pleet, M.L.; Enose-Akahata, Y.; Erickson, J.; Monaco, M.C.; Akpamagbo, Y.; Velluci, A.; Tanaka, Y.; Azodi, S.; Lepene, B.; et al. Viral antigens detectable in CSF exosomes from patients with retrovirus associated neurologic disease: Functional role of exosomes. *Clin. Transl. Med.* **2018**, *7*, e24. [CrossRef] [PubMed]

250. Pesce, E.; Manfrini, N.; Cordiglieri, C.; Santi, S.; Bandera, A.; Gobbini, A.; Gruarin, P.; Favalli, A.; Bombaci, M.; Cuomo, A.; et al. Exosomes Recovered From the Plasma of COVID-19 Patients Expose SARS-CoV-2 Spike-Derived Fragments and Contribute to the Adaptive Immune Response. *Front. Immunol.* **2022**, *12*, 785941. [CrossRef]
251. Huda, M.N.; Nurunnabi, M. Potential Application of Exosomes in Vaccine Development and Delivery. *Pharm. Res.* **2022**, *39*, 2635-2671. [CrossRef] [PubMed]

252. Sabanovic, B.; Piva, F.; Cecati, M.; Giulietti, M. Promising Extracellular Vesicle-Based Vaccines against Viruses, Including SARS-CoV-2. *Biology* **2021**, *10*, 94. [CrossRef] [PubMed]

253. Alphandéry, E. Nano dimensions/adjuvants in COVID-19 vaccines. *J. Mater. Chem. B* **2022**, *10*, 1520-1552. [CrossRef] [PubMed]

254. Jesus, S.; Soares, E.; Cruz, M.T.; Borges, O. Exosomes as adjuvants for the recombinant hepatitis B antigen: First report. *Eur. J. Pharm. Biopharm.* **2018**, *133*, 1-11. [CrossRef] [PubMed]

255. Vallhov, H.; Gutzeit, C.; Johansson, S.M.; Nagy, N.; Paul, M.; Li, Q.; Friend, S.; George, T.C.; Klein, E.; Scheynius, A.; et al. Exosomes Containing Glycoprotein 350 Released by EBV-Transformed B Cells Selectively Target B Cells through CD21 and Block EBV Infection In Vitro. *J. Immunol.* **2011**, *186*, 73-82. [CrossRef] [PubMed]

256. Delcayre, A.; Estelles, A.; Sperinde, J.; Roulon, T.; Paz, P.; Aguilar, B.; Villanueva, J.; Khine, S.; Le Pecq, J.-B. Exosome Display technology: Applications to the development of new diagnostics and therapeutics. *Blood Cells. Mol. Dis.* **2005**, *35*, 158-168. [CrossRef] [PubMed]

257. Bliss, C.M.; Parsons, A.J.; Nachbagauer, R.; Hamilton, J.R.; Cappuccini, F.; Ulaszewska, M.; Webber, J.P.; Clayton, A.; Hill, A.V.; Coughlan, L. Targeting Antigen to the Surface of EVs Improves the In Vivo Immunogenicity of Human and Non-human Adenoviral Vaccines in Mice. *Mol. Ther.—Methods Clin. Dev.* **2020**, *16*, 108-125. [CrossRef]

258. Stickney, Z.; Losacco, J.; McDevitt, S.; Zhang, Z.; Lu, B. Development of exosome surface display technology in living human cells. *Biochem. Biophys. Res. Commun.* **2016**, *472*, 53-59. [CrossRef]

259. Zhang, J.; Brown, A.; Johnson, B.; Diebold, D.; Asano, K.; Marriott, G.; Lu, B. Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake. *Pharmaceutics* **2022**, *14*, 2564. [CrossRef]

260. Dooley, K.; McConnell, R.E.; Xu, K.; Lewis, N.D.; Haupt, S.; Youniss, M.R.; Martin, S.; Sia, C.L.; McCoy, C.; Moniz, R.J.; et al. A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties. *Mol. Ther.* **2021**, *29*, 1729-1743. [CrossRef]

261. Xu, X.; Liang, Y.; Li, X.; Ouyang, K.; Wang, M.; Cao, T.; Li, W.; Liu, J.; Xiong, J.; Li, B.; et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. *Biomaterials* **2021**, *269*, 120539. [CrossRef] [PubMed]

262. Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J.A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. *Nat. Biotechnol.* **2011**, *29*, 341-345. [CrossRef] [PubMed]

263. Lin, Y.; Yan, M.; Bai, Z.; Xie, Y.; Ren, L.; Wei, J.; Zhu, D.; Wang, H.; Liu, Y.; Luo, J.; et al. Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy. *J. Nanobiotechnology* **2022**, *20*, 432. [CrossRef] [PubMed]

264. Wang, C.; Chen, Y.; Hu, S.; Liu, X. Insights into the function of ESCRT and its role in enveloped virus infection. *Front. Microbiol.* **2023**, *14*, 1261651. [CrossRef] [PubMed]

265. Zubarev, I.; Vladimirtsev, D.; Vorontsova, M.; Blatov, I.; Shevchenko, K.; Zvereva, S.; Lunev, E.A.; Faizuloev, E.; Barlev, N. Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes. *Cells* **2021**, *10*, 3043. [CrossRef]

266. Degassart, A.; Trentin, B.; Martin, M.; Hocquellet, A.; Bettebobillo, P.; Mamoun, R.; Vidal, M. Exosomal sorting of the cytoplasmic domain of bovine leukemia virus TM Env protein. *Cell Biol. Int.* **2009**, *33*, 36-48. [CrossRef]

267. Antes, T.J.; Middleton, R.C.; Luther, K.M.; Ijichi, T.; Peck, K.A.; Liu, W.J.; Valle, J.; Echavez, A.K.; Marbán, E. Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display. *J. Nanobiotechnol.* **2018**, *16*, 61. [CrossRef]

268. Zheng, W.; Schürz, M.; Wiklander, R.J.; Gustafsson, O.; Gupta, D.; Slovak, R.; Traista, A.; Coluzzi, A.; Roudi, S.; Barone, A.; et al. Surface display of functional moieties on extracellular vesicles using lipid anchors. *J. Control. Release* **2023**, *357*, 630-640. [CrossRef]

269. Kooijmans, S.A.A.; Aleza, C.G.; Roffler, S.R.; Van Solinge, W.W.; Vader, P.; Schiffelers, R.M. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. *J. Extracell. Vesicles* **2016**, *5*, 31053. [CrossRef]

270. Uppu, D.S.; Min, Y.; Kim, I.; Kumar, S.; Park, J.; Cho, Y.-K. Glycolipid-Anchored Proteins on Bioengineered Extracellular Vesicles for Lipopolysaccharide Neutralization. *ACS Appl. Mater. Interfaces* **2021**, *13*, 29313-29324. [CrossRef] [PubMed]

271. Anticoli, S.; Falcone, E.; Ruggieri, A.; Federico, M. Engineered exosomes boost the HCV NS3-specific CD8+ T lymphocyte immunity in humans. *Trials Vaccinol.* **2016**, *5*, 105-110. [CrossRef]

272. Anticoli, S.; Manfredi, F.; Chiozzini, C.; Arenaccio, C.; Olivetta, E.; Ferrantelli, F.; Capocefalo, A.; Falcone, E.; Ruggieri, A.; Federico, M. An Exosome-Based Vaccine Platform Imparts Cytotoxic T Lymphocyte Immunity against Viral Antigens. *Biotechnol. J.* **2018**, *13*, 1700443. [CrossRef]

273. Matsuzaka, Y.; Yashiro, R. Extracellular Vesicle-Based SARS-CoV-2 Vaccine. *Vaccines* **2023**, *11*, 539. [CrossRef]

274. Cacciottolo, M.; Nice, J.B.; Li, Y.; LeClaire, M.J.; Twaddle, R.; Mora, C.L.; Adachi, S.Y.; Chin, E.R.; Young, M.; Angeles, J.; et al. Exosome-Based Multivalent Vaccine: Achieving Potent Immunization, Broadened Reactivity, and Strong T-Cell Responses with Nanograms of Proteins. *Microbiol. Spectr.* **2023**, *11*, e00503-23. [CrossRef] [PubMed]

275. Tsai, S.J.; Atai, N.A.; Cacciottolo, M.; Nice, J.; Salehi, A.; Guo, C.; Sedgwick, A.; Kanagavelu, S.; Gould, S.J. Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity. *J. Biol. Chem.* **2021**, *297*, 101266. [CrossRef] [PubMed]
251. Huda, M.N.; Nurunnabi, M. Potential Application of Exosomes in Vaccine Development and Delivery. *Pharm. Res.* **2022**, *39*, 2635–2671. [CrossRef] [PubMed]

252. Sabanovic, B.; Piva, F.; Cecati, M.; Giulietti, M. Promising Extracellular Vesicle-Based Vaccines against Viruses, Including SARS-CoV-2. *Biology* **2021**, *10*, 94. [CrossRef] [PubMed]

253. Alphandéry, E. Nano dimensions/adjuvants in COVID-19 vaccines. *J. Mater. Chem. B* **2022**, *10*, 1520–1552. [CrossRef] [PubMed]

254. Jesus, S.; Soares, E.; Cruz, M.T.; Borges, O. Exosomes as adjuvants for the recombinant hepatitis B antigen: First report. *Eur. J. Pharm. Biopharm.* **2018**, *133*, 1–11. [CrossRef] [PubMed]

255. Vallhov, H.; Gutzeit, C.; Johansson, S.M.; Nagy, N.; Paul, M.; Li, Q.; Friend, S.; George, T.C.; Klein, E.; Scheynius, A.; et al. Exosomes Containing Glycoprotein 350 Released by EBV-Transformed B Cells Selectively Target B Cells through CD21 and Block EBV Infection In Vitro. *J. Immunol.* **2011**, *186*, 73–82. [CrossRef] [PubMed]

256. Delcayre, A.; Estelles, A.; Sperinde, J.; Roulon, T.; Paz, P.; Aguilar, B.; Villanueva, J.; Khine, S.; Le Pecq, J.-B. Exosome Display technology: Applications to the development of new diagnostics and therapeutics. *Blood Cells. Mol. Dis.* **2005**, *35*, 158–168. [CrossRef] [PubMed]

257. Bliss, C.M.; Parsons, A.J.; Nachbagauer, R.; Hamilton, J.R.; Cappuccini, F.; Ulaszewska, M.; Webber, J.P.; Clayton, A.; Hill, A.V.; Coughlan, L. Targeting Antigen to the Surface of EVs Improves the In Vivo Immunogenicity of Human and Non-human Adenoviral Vaccines in Mice. *Mol. Ther.—Methods Clin. Dev.* **2020**, *16*, 108–125. [CrossRef]

258. Stickney, Z.; Losacco, J.; McDevitt, S.; Zhang, Z.; Lu, B. Development of exosome surface display technology in living human cells. *Biochem. Biophys. Res. Commun.* **2016**, *472*, 53–59. [CrossRef]

259. Zhang, J.; Brown, A.; Johnson, B.; Diebold, D.; Asano, K.; Marriott, G.; Lu, B. Genetically Engineered Extracellular Vesicles Harboring Transmembrane Scaffolds Exhibit Differences in Their Size, Expression Levels of Specific Surface Markers and Cell-Uptake. *Pharmaceutics* **2022**, *14*, 2564. [CrossRef]

260. Dooley, K.; McConnell, R.E.; Xu, K.; Lewis, N.D.; Haupt, S.; Youniss, M.R.; Martin, S.; Sia, C.L.; McCoy, C.; Moniz, R.J.; et al. A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties. *Mol. Ther.* **2021**, *29*, 1729–1743. [CrossRef]

261. Xu, X.; Liang, Y.; Li, X.; Ouyang, K.; Wang, M.; Cao, T.; Li, W.; Liu, J.; Xiong, J.; Li, B.; et al. Exosome-mediated delivery of kartogenin for chondrogenesis of synovial fluid-derived mesenchymal stem cells and cartilage regeneration. *Biomaterials* **2021**, *269*, 120539. [CrossRef] [PubMed]

262. Alvarez-Erviti, L.; Seow, Y.; Yin, H.; Betts, C.; Lakhal, S.; Wood, M.J.A. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. *Nat. Biotechnol.* **2011**, *29*, 341–345. [CrossRef] [PubMed]

263. Lin, Y.; Yan, M.; Bai, Z.; Xie, Y.; Ren, L.; Wei, J.; Zhu, D.; Wang, H.; Liu, Y.; Luo, J.; et al. Huc-MSC-derived exosomes modified with the targeting peptide of aHSCs for liver fibrosis therapy. *J. Nanobiotechnology* **2022**, *20*, 432. [CrossRef] [PubMed]

264. Wang, C.; Chen, Y.; Hu, S.; Liu, X. Insights into the function of ESCRT and its role in enveloped virus infection. *Front. Microbiol.* **2023**, *14*, 1261651. [CrossRef] [PubMed]

265. Zubarev, I.; Vladimirtsev, D.; Vorontsova, M.; Blatov, I.; Shevchenko, K.; Zvereva, S.; Lunev, E.A.; Faizuloev, E.; Barlev, N. Viral Membrane Fusion Proteins and RNA Sorting Mechanisms for the Molecular Delivery by Exosomes. *Cells* **2021**, *10*, 3043. [CrossRef]

266. Degassart, A.; Trentin, B.; Martin, M.; Hocquellet, A.; Bettebobillo, P.; Mamoun, R.; Vidal, M. Exosomal sorting of the cytoplasmic domain of bovine leukemia virus TM Env protein. *Cell Biol. Int.* **2009**, *33*, 36–48. [CrossRef]

267. Antes, T.J.; Middleton, R.C.; Luther, K.M.; Ijichi, T.; Peck, K.A.; Liu, W.J.; Valle, J.; Echavez, A.K.; Marbán, E. Targeting extracellular vesicles to injured tissue using membrane cloaking and surface display. *J. Nanobiotechnol.* **2018**, *16*, 61. [CrossRef]

268. Zheng, W.; Schürz, M.; Wiklander, R.J.; Gustafsson, O.; Gupta, D.; Slovak, R.; Traista, A.; Coluzzi, A.; Roudi, S.; Barone, A.; et al. Surface display of functional moieties on extracellular vesicles using lipid anchors. *J. Control. Release* **2023**, *357*, 630–640. [CrossRef]

269. Kooijmans, S.A.A.; Aleza, C.G.; Roffler, S.R.; Van Solinge, W.W.; Vader, P.; Schiffelers, R.M. Display of GPI-anchored anti-EGFR nanobodies on extracellular vesicles promotes tumour cell targeting. *J. Extracell. Vesicles* **2016**, *5*, 31053. [CrossRef]

270. Uppu, D.S.; Min, Y.; Kim, I.; Kumar, S.; Park, J.; Cho, Y.-K. Glycolipid-Anchored Proteins on Bioengineered Extracellular Vesicles for Lipopolysaccharide Neutralization. *ACS Appl. Mater. Interfaces* **2021**, *13*, 29313–29324. [CrossRef] [PubMed]

271. Anticoli, S.; Falcone, E.; Ruggieri, A.; Federico, M. Engineered exosomes boost the HCV NS3-specific CD8+ T lymphocyte immunity in humans. *Trials Vaccinol.* **2016**, *5*, 105–110. [CrossRef]

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274. Cacciottolo, M.; Nice, J.B.; Li, Y.; LeClaire, M.J.; Twaddle, R.; Mora, C.L.; Adachi, S.Y.; Chin, E.R.; Young, M.; Angeles, J.; et al. Exosome-Based Multivalent Vaccine: Achieving Potent Immunization, Broadened Reactivity, and Strong T-Cell Responses with Nanograms of Proteins. *Microbiol. Spectr.* **2023**, *11*, e00503-23. [CrossRef] [PubMed]

275. Tsai, S.J.; Atai, N.A.; Cacciottolo, M.; Nice, J.; Salehi, A.; Guo, C.; Sedgwick, A.; Kanagavelu, S.; Gould, S.J. Exosome-mediated mRNA delivery in vivo is safe and can be used to induce SARS-CoV-2 immunity. *J. Biol. Chem.* **2021**, *297*, 101266. [CrossRef] [PubMed]
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277. Zhang, Q.; Wang, M.; Han, C.; Wen, Z.; Meng, X.; Qi, D.; Wang, N.; Du, H.; Wang, J.; Lu, L.; et al. Intraduodenal Delivery of Exosome-Loaded SARS-CoV-2 RBD mRNA Induces a Neutralizing Antibody Response in Mice. *Vaccines* **2023**, *11*, 673. [CrossRef]

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279. Karn, V.; Ahmed, S.; Tsai, L.-W.; Dubey, R.; Ojha, S.; Singh, H.N.; Kumar, M.; Gupta, P.K.; Sadhu, S.; Jha, N.K.; et al. Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects. *Biomedicines* **2021**, *9*, 1373. [CrossRef] [PubMed]

280. Wang, Z.; Popowski, K.D.; Zhu, D.; Abad, B.L.d.J.; Wang, X.; Liu, M.; Lutz, H.; De Naeyer, N.; DeMarco, C.T.; Denny, T.N.; et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. *Nat. Biomed. Eng.* **2022**, *6*, 791–805. [CrossRef]

281. Schorey, J.S.; Cheng, Y.; Singh, P.P.; Smith, V.L. Exosomes and other extracellular vesicles in host-pathogen interactions. *EMBO Rep.* **2015**, *16*, 24–43. [CrossRef] [PubMed]

282. Schwab, A.; Meyering, S.S.; Lepene, B.; Iordanskiy, S.; van Hoek, M.L.; Hakami, R.M.; Kashanchi, F. Extracellular vesicles from infected cells: Potential for direct pathogenesis. *Front. Microbiol.* **2015**, *6*, 1132. [CrossRef] [PubMed]

283. Lai, R.C.; Yeo, R.W.Y.; Tan, K.H.; Lim, S.K. Exosomes for drug delivery—A novel application for the mesenchymal stem cell. *Biotechnol. Adv.* **2013**, *31*, 543–551. [CrossRef] [PubMed]

284. Tumban, E. Bacteriophage Virus-Like Particles: Platforms for Vaccine Design. In *Bacteriophages*; Methods in Molecular Biology; Springer: New York, NY, USA, 2024; pp. 411–423. [CrossRef]

285. Celis-Giraldo, C.T.; López-Abán, J.; Muro, A.; Patarroyo, M.A.; Manzano-Román, R. Nanovaccines against Animal Pathogens: The Latest Findings. *Vaccines* **2021**, *9*, 988. [CrossRef] [PubMed]

286. Marcus, M.; Leonard, J. FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver. *Pharmaceuticals* **2013**, *6*, 659–680. [CrossRef]

287. Wang, X.; Xia, J.; Yang, L.; Dai, J.; He, L. Recent progress in exosome research: Isolation, characterization and clinical applications. *Cancer Gene Ther.* **2023**, *30*, 1051–1065. [CrossRef]

288. Fu, C.; Zhou, L.; Mi, Q.-S.; Jiang, A. Plasmacytoid Dendritic Cells and Cancer Immunotherapy. *Cells* **2022**, *11*, 222. [CrossRef]

289. Shahraki, K.; Boroumand, P.G.; Lotfi, H.; Radnia, F.; Shahriari, H.; Sargazi, S.; Mortazavi, S.S.; Shirvaliloo, M.; Shirvalilou, S.; Sheervalilou, R. An update in the applications of exosomes in cancer theranostics: From research to clinical trials. *J. Cancer Res. Clin. Oncol.* **2023**, *149*, 8087–8116. [CrossRef]

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
276. Popowski, K.D.; Moatti, A.; Scull, G.; Silkstone, D.; Lutz, H.; Abad, B.L.d.J.; George, A.; Belcher, E.; Zhu, D.; Mei, X.; et al. Inhalable dry powder mRNA vaccines based on extracellular vesicles. *Matter* **2022**, *5*, 2960–2974. [CrossRef] [PubMed]

277. Zhang, Q.; Wang, M.; Han, C.; Wen, Z.; Meng, X.; Qi, D.; Wang, N.; Du, H.; Wang, J.; Lu, L.; et al. Intraduodenal Delivery of Exosome-Loaded SARS-CoV-2 RBD mRNA Induces a Neutralizing Antibody Response in Mice. *Vaccines* **2023**, *11*, 673. [CrossRef]

278. Kuate, S.; Cinatl, J.; Doerr, H.W.; Überla, K. Exosomal vaccines containing the S protein of the SARS coronavirus induce high levels of neutralizing antibodies. *Virology* **2007**, *362*, 26–37. [CrossRef] [PubMed]

279. Karn, V.; Ahmed, S.; Tsai, L.-W.; Dubey, R.; Ojha, S.; Singh, H.N.; Kumar, M.; Gupta, P.K.; Sadhu, S.; Jha, N.K.; et al. Extracellular Vesicle-Based Therapy for COVID-19: Promises, Challenges and Future Prospects. *Biomedicines* **2021**, *9*, 1373. [CrossRef] [PubMed]

280. Wang, Z.; Popowski, K.D.; Zhu, D.; Abad, B.L.d.J.; Wang, X.; Liu, M.; Lutz, H.; De Naeyer, N.; DeMarco, C.T.; Denny, T.N.; et al. Exosomes decorated with a recombinant SARS-CoV-2 receptor-binding domain as an inhalable COVID-19 vaccine. *Nat. Biomed. Eng.* **2022**, *6*, 791–805. [CrossRef]

281. Schorey, J.S.; Cheng, Y.; Singh, P.P.; Smith, V.L. Exosomes and other extracellular vesicles in host-pathogen interactions. *EMBO Rep.* **2015**, *16*, 24–43. [CrossRef] [PubMed]

282. Schwab, A.; Meyering, S.S.; Lepene, B.; Iordanskiy, S.; van Hoek, M.L.; Hakami, R.M.; Kashanchi, F. Extracellular vesicles from infected cells: Potential for direct pathogenesis. *Front. Microbiol.* **2015**, *6*, 1132. [CrossRef] [PubMed]

283. Lai, R.C.; Yeo, R.W.Y.; Tan, K.H.; Lim, S.K. Exosomes for drug delivery—A novel application for the mesenchymal stem cell. *Biotechnol. Adv.* **2013**, *31*, 543–551. [CrossRef] [PubMed]

284. Tumban, E. Bacteriophage Virus-Like Particles: Platforms for Vaccine Design. In *Bacteriophages*; Methods in Molecular Biology; Springer: New York, NY, USA, 2024; pp. 411–423. [CrossRef]

285. Celis-Giraldo, C.T.; López-Abán, J.; Muro, A.; Patarroyo, M.A.; Manzano-Román, R. Nanovaccines against Animal Pathogens: The Latest Findings. *Vaccines* **2021**, *9*, 988. [CrossRef] [PubMed]

286. Marcus, M.; Leonard, J. FedExosomes: Engineering Therapeutic Biological Nanoparticles that Truly Deliver. *Pharmaceuticals* **2013**, *6*, 659–680. [CrossRef]

287. Wang, X.; Xia, J.; Yang, L.; Dai, J.; He, L. Recent progress in exosome research: Isolation, characterization and clinical applications. *Cancer Gene Ther.* **2023**, *30*, 1051–1065. [CrossRef]

288. Fu, C.; Zhou, L.; Mi, Q.-S.; Jiang, A. Plasmacytoid Dendritic Cells and Cancer Immunotherapy. *Cells* **2022**, *11*, 222. [CrossRef]

289. Shahraki, K.; Boroumand, P.G.; Lotfi, H.; Radnia, F.; Shahriari, H.; Sargazi, S.; Mortazavi, S.S.; Shirvaliloo, M.; Shirvalilou, S.; Sheervalilou, R. An update in the applications of exosomes in cancer theranostics: From research to clinical trials. *J. Cancer Res. Clin. Oncol.* **2023**, *149*, 8087–8116. [CrossRef]

**Disclaimer/Publisher's Note:** The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.