How Engineered Exosomes Can Impact Targeted Therapies

Exosomes—small, naturally secreted extracellular vesicles (EVs)—are rapidly gaining momentum in biopharmaceutical research as versatile delivery vehicles for complex therapeutic payloads (1). Once considered merely cellular waste carriers, these nanoparticles are now central to next‑generation drug delivery strategies aimed at transporting nucleic acids, proteins, gene‑editing systems, and other advanced modalities (2).

The potential of exosomes to overcome longstanding barriers in drug targeting and delivery has made them increasingly relevant to the biopharma manufacturing sector, particularly as developers seek scalable, low‑immunogenic, and precise systems for future therapies (3). Current research efforts are exploring the use of engineered exosomes to optimize drug delivery (4).

How are exosomes used in drug development?

Exosomes are released by nearly all cell types in the body and are involved in intercellular communication. Their natural ability to transfer proteins, RNA species, and signaling molecules makes them attractive candidates for therapeutic delivery (1). In biopharmaceutical R&D, engineered exosomes are increasingly being designed to transport nucleic acids, such as messenger RNA, small interfering RNA, or antisense oligonucleotides. In addition, engineered exosomes are being explored as delivery vehicles for therapeutic proteins and clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein (CRISPR/Cas) gene‑editing components (2,4).

Researchers are also improving exosome functionalization. Surface engineering, in which targeted peptides are incorporated as ligands to direct vesicles toward specific tissues or cell types, is a promising direction for exosome use (5). This engineering strategy strengthens the selectivity of exosome‑mediated delivery and may reduce off‑target dosing (6).

What industry need do engineered exosomes address?

Specifically, engineered exosomes address the critical need in biopharma for delivery vehicles that combine the natural biocompatibility and barrier-crossing capacity of naturally occurring cell-derived exosomes with the enhanced cargo loading, stability, and targeting precision that can be built into their engineered counterpart (7). By applying bioengineering techniques, such as genetically modifying source cells or chemically modifying exosome surfaces, scientists can load exosomes with therapeutic cargos more efficiently and minimize such issues as rapid clearance or low payload capacity typically seen with naïve exosomes (7).

Engineered exosomes can also be decorated with tissue- or cell-specific ligands (e.g., brain-targeting peptides) or surface markers that direct them to disease-relevant sites. This characteristic improves upon the sometimes-insufficient targeting ability of natural exosomes (8). Engineered exosomes make targeted therapy for the brain, heart, tumors, or other organs (8,9).

Rather than relying on passive distribution, engineered exosomes can, thus, offer a programmable and precise delivery platform with the ability to overcome biological barriers, improve therapeutic index, and potentially enable treatments for hard-to-reach tissues, such as the central nervous system (CNS) or dense tumor microenvironments (10).

What analytical and bioprocessing challenges limit drug development?

Manufacturing and analytical bottlenecks are currently the major obstacles to the clinical translation of engineered exosomes (11). Natural exosomes are a mixed population with overlapping sizes, densities, and cargos; this biological heterogeneity makes defining identity, purity, and potency difficult (12).

In addition, limited and imperfect characterization tools restrict robust quality control (13). Widely used characterization techniques, such as nanoparticle tracking analysis, dynamic light scattering, electron microscopy, and protein marker immunoblots, typically provide partial, method-dependent views of size, concentration, and composition (14). These techniques, however, lack absolute specificity and struggle to resolve co-isolated non-EV contaminants or to quantify cargo stoichiometry (e.g., how many copies of siRNA or protein molecules are carried per vesicle) (15).

Meanwhile, assays that evaluate potency and mechanism-of-action (MoA) remain underdeveloped, and regulators expect reliable potency assays that reflect the therapeutic MoA (16). But because engineered exosomes can act via delivery, surface signaling, or immunomodulation—and sometimes simultaneously—establishing a single, predictive potency readout becomes elusive, making the development of validated bioassays that correlate with in-vivo efficacy a widespread unmet need (16).

On the bioprocessing side, achieving scalable and reproducible production is a core challenge (17). Cell source selection, culture format (e.g., adherent vs. suspension cell culture; bioreactors), and cellular stress or media composition crucially impact the quality and quantity of the exosomes; therefore, production requires tight upstream control to ensure batch consistency (18). Moreover, techniques that work at lab scale do not necessarily translate easily to commercial-scale production; for example, scalable separations, such as tangential flow filtration, size-exclusion chromatography, affinity capture, etc., may be promising but require optimization to balance yield, purity, and cost (19).

Meanwhile, regulatory and standardization gaps amplify development risk in that reference materials, harmonized analytical standards, and clear chemistry, manufacturing, and controls expectations are limited. Regulations and standards for exosomes vary, according to the jurisdiction of different world regions, meaning sponsors must engage in dialogue with regulators in each region they intend to market their product to agree on release criteria and comparability strategies (16).

Progress in engineered exosome-based drug development, therefore, requires coordinated advances in single-vesicle analytics, validated potency assays tied to MoA, scalable good manufacturing practice (GMP) processes that preserve engineered features, and regulatory/scientific standardization, which, if achieved, would reliably move forward the progress of engineered exosomes from promising research tools to reproducible approved therapeutics (12).

What are the implications if engineered exosome therapeutics succeed commercially?

Commercial success of engineered exosome therapeutics could present the biopharma industry with both strategic opportunity and practical disruption across R&D, manufacturing, and clinical practice (20). Because engineered exosomes promise cell-specific delivery of therapeutic cargo while exhibiting low immunogenicity and the ability to traverse such barriers as the blood–brain barrier, they could expand the druggable space for CNS, oncologic, and genetic indications currently limited by delivery challenges (21).

On the clinical front, exosome platforms could enable smaller, more targeted payloads with improved therapeutic indices, potentially shifting development priorities from broadly cytotoxic approaches toward precision intracellular modulation and protein replacement strategies (22). Widespread clinical adoption would likely prompt a retooling of clinical trial design to capture delivery-dependent endpoints, companion diagnostics for targeting, and real-world monitoring of long-term biodistribution, which could collectively reshape translational strategy and commercial models across the industry (22).

Economically, successful exosome products would drive demand for standardized upstream cell lines, GMP-grade cell culture systems, and specialized downstream purification and characterization workflows—all of which could create new supplier ecosystems but would also necessitate substantial capital investment to validate scalable, reproducible manufacturing (13). Finally, regulatory pathways would need to evolve, meaning regulators would require robust assays for potency, identity, and impurity profiling of heterogeneous extracellular vesicle preparations, as well as rigorous safety datasets addressing biodistribution and off-target effects (23).

References

1. Rajput, A.; Varshney, A.; Bajaj, R.; Pokharkar V. Exosomes as New Generation Vehicles for Drug Delivery: Biomedical Applications and Future Perspectives. Molecules 2022, 27 (21), 7289. DOI: 10.3390/molecules27217289
2. Butreddy, A.; Kommineni, N.; Dudhipala, N. Exosomes as Naturally Occurring Vehicles for Delivery of Biopharmaceuticals: Insights from Drug Delivery to Clinical Perspectives. Nanomaterials (Basel) 2021, 11 (6), 1481. DOI: 10.3390/nano11061481
3. Kim, H. I.; Park, J.; Zhu, Y.; et al. Recent Advances in Extracellular Vesicles for Therapeutic Cargo Delivery. Exp. Mol. Med. 2024, 56, 836–849. DOI: 10.1038/s12276-024-01201-6
4. Schwarz, G.; Ren, X.; Xie, W.; et al. Engineered Exosomes: A Promising Drug Delivery Platform with Therapeutic Potential. Front. Mol. Biosci. 2025, 12–2025. DOI: 10.3389/fmolb.2025.1583992
5. Liu, X.; Yang, X.; Sun, W.; et al. Systematic Evolution of Ligands by Exosome Enrichment: A Proof-of-Concept Study for Exosome-Based Targeting Peptide Screening. Adv. Biosyst. 2019, 3 (2), e1800275. DOI: 10.1002/adbi.201800275
6. Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering Exosomes for Targeted Drug Delivery. Theranostics 2021, 11 (7), 3183–3195. DOI: 10.7150/thno.52570
7. Chen, Z.; Xiong, M.; Tian, J.; et al. Encapsulation and Assessment of Therapeutic Cargo in Engineered Exosomes: A Systematic Review. J. Nanobiotechnol 2024, 22 (18). DOI: 10.1186/s12951-023-02259-6
8. Xu, M.; Feng, T.; Liu, B.; et al. Engineered Exosomes: Desirable Target-Tracking Characteristics for Cerebrovascular and Neurodegenerative Disease Therapies. Theranostics 2021, 11 (18), 8926–8944. DOI: 10.7150/thno.62330
9. Pang, J-L.; Shao, H.; Xu, X-G; et al. Targeted Drug Delivery of Engineered Mesenchymal Stem/Stromal-Cell-Derived Exosomes in Cardiovascular Disease: Recent Trends and Future Perspectives. Front. Bioeng. Biotechnol. 2024, 12. DOI: 10.3389/fbioe.2024.1363742
10. Premchandani, T.; Tatode, A.; Taksande, J.; et al. Engineered Exosomes as Smart Drug Carriers: Overcoming Biological Barriers in CNS and Cancer Therapy. Drugs Drug Candidates 2025, 4, 19. DOI: 10.3390/ddc4020019
11. Lee, E. C.; Choi, D.; Lee, D. H.; Oh, J. S. Engineering Exosomes for CNS Disorders: Advances, Challenges, and Therapeutic Potential. Int. J. Mol. Sci. 2025, 26 (7), 3137. DOI: 10.3390/ijms26073137
12. Lai, J. J.; Chau, Z. L.; Chen, S. Y.; et al. Exosome Processing and Characterization Approaches for Research and Technology Development. Adv Sci (Weinh) 2022, 9 (15), e2103222. DOI: 10.1002/advs.202103222
13. Palakurthi, S. S.; Shah, B.; Kapre, S.; et al. A Comprehensive Review of Challenges and Advances in Exosome-Based Drug Delivery Systems. Nanoscale Adv. 2024, 6, 5803–5826. DOI: 10.1039/D4NA00501E
14. Zhou, M.; Weber, S. R.; Zhao, Y.; et al. Chapter 2—Methods for Exosome Isolation and Characterization in Exosomes; Editor(s), Edelstein, L.; Smythies, J.; Quesenberry, P.; Noble, D.; Academic Press, 2020, pp 23–38, DOI: 10.1016/B978-0-12-816053-4.00002-X
15. Li, X.; Corbett, A. L.; Taatizadeh, E.; et al. Challenges and Opportunities in Exosome Research—Perspectives from Biology, Engineering, and Cancer Therapy. APL Bioeng. 2019, 3 (1), 011503. DOI: 10.1063/1.5087122
16. Wang, C. K.; Tsai, T. H.; Lee, C. H. Regulation of Exosomes as Biologic Medicines: Regulatory Challenges Faced in Exosome Development and Manufacturing Processes. Clin. Transl. Sci. 2024, 17 (8), e13904. DOI: 10.1111/cts.13904
17. Ahn, S. H.; Ryu, S. W.; Choi, H.; et al. Manufacturing Therapeutic Exosomes: from Bench to Industry. Mol Cells. 2022, 45 (5), 284–290. DOI: 10.14348/molcells.2022.2033
18. Paganini, C.; Boyce, H.; Libort, G.; Arosio, P. High-Yield Production of Extracellular Vesicle Subpopulations with Constant Quality Using Batch-Refeed Cultures. Adv. Healthcare Mater. 2023, 12 (8), 2202232. DOI: 10.1002/adhm.202202232
19. Chen, J.; Li, P.; Zhang, T.; et al. Review on Strategies and Technologies for Exosome Isolation and Purification. Front. Bioeng. Biotechnol. 2022, 9-2021. DOI: 10.3389/fbioe.2021.811971
20. Ma, Y.; Dong, S.; Grippin, A. J.; et al. Engineering Therapeutical Extracellular Vesicles for Clinical Translation. Trends Biotechnol. 2025, 43 (1), 61–82. DOI: 10.1016/j.tibtech.2024.08.007
21. Huang, L.; Wu, E.; Liao, J.; et al. Research Advances of Engineered Exosomes as Drug Delivery Carrier. ACS Omega 2023, 8 (46), 43374–43387. DOI: 10.1021/acsomega.3c04479
22. Kim, M.; Choi, H.; Jang, D-J.; et al. Exploring the Clinical Transition of Engineered Exosomes Designed for Intracellular Delivery of Therapeutic Proteins. Stem Cells Transl. Med. 2024, 13 (7), 637–647. DOI: 10.1093/stcltm/szae02727
23. Ghodasara, A.; Raza, A.; Wolfram, J.; et al. Clinical Translation of Extracellular Vesicles. Adv. Healthcare Mater. 2023, 12 (28), 2301010. DOI: 10.1002/adhm.202301010