Extracellular Vesicles Targeting Cancer Signaling Networks and Drug Delivery
Background
Cancer cells do not grow solely through mutations. They continuously send signals to surrounding immune cells, fibroblasts, and endothelial cells to alter the tumor microenvironment in their favor. In this process, extracellular vesicles (EVs) have emerged as key transporters. These are nanometer-sized lipid membrane particles secreted by almost all cells, delivering biomolecules such as proteins, lipids, DNA, messenger RNA, and microRNA to other cells.
Cancer-derived EVs regulate tumor initiation, growth, angiogenesis, immune evasion, and drug resistance. They can travel through the bloodstream to distant organs and preform the premetastatic niche. Conversely, EVs can be harnessed as therapeutic agents due to their biocompatibility and ability to enter cells, enabling targeted drug delivery to desired tissues. Their abundance in bodily fluids such as blood and urine, and their reflection of the molecular characteristics of the secreting cell, also make them attractive as liquid biopsy biomarkers.
However, EVs vary in size, composition, and biogenesis pathways. Different subpopulations such as exosomes and microvesicles are separated and quantified using methods that differ across research institutions, making direct comparison of results difficult. This review organizes EV-based therapeutic research for six cancer types—breast, lung, colorectal, prostate, pancreatic, and glioblastoma—according to their physicochemical properties, engineering modifications, cargo, and mechanisms of action.
Key Findings
The therapeutic strategies proposed by the researchers are broadly divided into two approaches. First, blocking the production, release, or uptake of tumor-derived EVs to disrupt cancer cell communication. This approach may simultaneously weaken signals involved in metastasis, immune suppression, and treatment resistance, but it carries the risk of also interfering with EV functions in normal cells.
The second strategy uses EVs themselves as drug delivery vehicles. Their lipid bilayer, similar to cell membranes, can encapsulate both hydrophilic nucleic acids and hydrophobic small-molecule drugs, protecting them from degradation in the body and facilitating their delivery into target cells. The review includes preclinical formulations carrying chemotherapeutic agents such as doxorubicin, paclitaxel, and gemcitabine, as well as small interfering RNA (siRNA), microRNA, and gene-editing tools. Attaching peptides, antibodies, or aptamers that recognize tumor receptors to the EV surface can enhance uptake by specific cancer cells.
Clinical development is still in its early stages. Notable examples include a phase I trial delivering siRNA targeting the KRAS G12D mutation in mesenchymal stromal cell-derived EVs to pancreatic cancer patients, and phase I/II trials of engineered EVs carrying STING agonists to stimulate innate immune pathways. Approaches using dendritic cell-derived EVs as cancer vaccines have also been evaluated in lung cancer. However, this paper is a review that synthesizes various formulations and clinical cases, not a study presenting new animal experiments or patient efficacy data. The results should not be interpreted as definitive evidence of therapeutic effectiveness.
Implications and Outlook
EVs have a dual nature: they are both pathological signals spread by cancer and a biological platform for delivering therapeutics. Their ability to serve as both a target for disruption and a therapeutic delivery system distinguishes them from synthetic nanoparticles. In particular, EVs can cross biological barriers such as the blood-brain barrier relatively well, making them valuable in the development of glioblastoma treatments.
The key to commercialization lies in large-scale production and quality control. The content of EVs can vary depending on the type and condition of the cultured cells, and protein aggregates or lipid particles may be introduced during the separation process. Even with the same particle count, the amount and biological activity of the effective cargo may differ, making dosage setting non-trivial. Common standards for cell sources, purity, efficacy testing, and storage stability, as well as long-term toxicity data, must be established. It must also be confirmed that EVs with enhanced tumor tropism do not accumulate in unexpected organs or carry tumor-promoting signals. In the near term, ensuring manufacturing consistency, safety, and actual drug delivery in early-phase clinical trials remains a core challenge.
Extracellular vesicles (EVs) are a diverse population of membrane nanoparticles secreted by nearly all cell types, playing a key role in intercellular communication by transferring bioactive macromolecular cargo. In cancer, EVs shape both the local tumour microenvironment and distant premetastatic niches. They are essential regulators of tumour initiation, progression, immune modulation, angiogenesis and metastatic dissemination. Due to their abundance in biofluids, EVs have attracted attention as diagnostic and prognostic biomarkers for early detection and assessment of therapeutic response. Additionally, EVs represent a promising therapeutic platform for delivering chemotherapeutic agents, nucleic acids and gene-editing tools, with enhanced specificity and reduced systemic toxicity. This review summarises current therapeutic applications of EVs across breast, lung, colorectal, prostate and pancreatic cancers and glioblastoma. Key findings are presented for each formulation, with emphasis on the EV physicochemical properties and engineered modifications, their cargo and mechanisms underlying their biological effects. Although the clinical translation of EV-based advances remains limited and challenging, this review highlights significant preclinical findings and examples of clinical trials where EVs have been used as therapeutic agents.
In the clinic, EVs can be developed as both therapeutic agents and companion diagnostics. For example, continuous measurement of mutant RNA or immune-suppressive proteins in tumor-derived EVs in the blood can track drug response and resistance emergence, while siRNA or chemotherapeutic agents tailored to a patient's molecular targets can be delivered via engineered EVs. In pancreatic cancer, EVs could serve as delivery vehicles for KRAS-targeting nucleic acids, and in glioblastoma, they could overcome the blood-brain barrier to deliver drugs. For pharmaceutical companies, establishing standardized production processes—from cell line development to culture, purification, and loading—and efficacy testing methods are top priorities. Clinical benefits will only be confirmed when comparative trials demonstrate that EV-based therapies achieve higher drug concentrations in tumors and lower systemic toxicity than existing treatments.