Exosome-mediated delivery of siRNA has emerged as a promising therapeutic strategy for cancer, offering precise gene silencing while minimizing off-target effects. Exosomes are naturally secreted extracellular vesicles that can carry RNA cargos and interact with recipient cells. Their biocompatible membranes protect siRNA from enzymatic degradation in circulation and support cellular uptake, making them attractive vehicles for therapeutic nucleic acids. This review synthesizes existing evidence on loading techniques, targeting strategies, observed therapeutic outcomes in preclinical systems, combination regimens, and early clinical findings, and it outlines principal translational challenges.
Exosomes possess intrinsic surface proteins such as integrins and tetraspanins that mediate adhesion and specific interactions within the tumor microenvironment. These surface molecules contribute to a degree of natural tropism for certain tissues and cell types, facilitating exosome uptake by tumor and stromal cells. The tumor microenvironment itself—comprising malignant cells, stromal elements, and immune components—can be targeted via exosome-mediated delivery because exosomes are readily internalized and can deliver functional siRNA payloads directly into recipient cells.
Multiple strategies have been developed to incorporate siRNA into exosomes. Approaches fall broadly into two categories: endogenous loading and exogenous loading. Endogenous loading typically involves engineering donor cells to express the desired siRNA or to enrich particular RNA species in secreted exosomes. Exogenous loading entails manipulating isolated exosomes to incorporate siRNA through techniques such as electroporation or chemical transfection. Hybrid systems that combine exosomes with synthetic nanoparticles have also been described to increase payload capacity and stability. Each method aims to balance loading efficiency, preservation of exosome integrity, and retention of biological activity of the siRNA.
Beyond natural tropism, exosome targeting has been enhanced by engineering surface features and by creating hybrid exosome–nanoparticle constructs. Surface functionalization strategies include decorating exosome membranes with targeting ligands or peptides to improve tumor-homing efficiency and cellular specificity. These engineering methods seek to augment stability, increase selective uptake by tumor cells, and reduce off-target distribution. Hybrid exosome–nanoparticle systems are used to leverage the favorable biocompatibility of exosomes together with the tunable properties and payload capacity of synthetic carriers.
Preclinical data summarized in the review indicate that exosome-delivered siRNAs can achieve suppression of oncogenes, inhibition of tumor growth, reversal of chemoresistance, and modulation of immune responses. Delivery to tumor cells and components of the tumor microenvironment allows silencing of survival pathways and can lead to increased apoptosis or reduced proliferation in experimental models. Exosome vectors have been used to target both tumor-intrinsic drivers and stromal or immune elements that support tumor progression.
Combination approaches pairing exosome-mediated siRNA with conventional or advanced modalities have shown synergistic potential in preclinical contexts. Combining siRNA delivery with chemotherapy can simultaneously inhibit resistance mechanisms while cytotoxic agents reduce tumor burden. Integration with immunotherapy or strategies that remodel the immunosuppressive microenvironment may amplify antitumor immune responses. Phototherapy combined with exosome-siRNA approaches has also been explored to potentiate tumor cell killing. These multimodal regimens aim to concurrently disrupt survival signaling, promote apoptosis, and alter the tumor milieu to improve therapeutic efficacy.
Early-phase clinical studies referenced in the review report observations of safety, demonstrable biodistribution, and functional gene silencing after exosome administration, supporting translational potential. These initial clinical experiences suggest that exosome-mediated siRNA therapeutics can be delivered in human subjects with measurable biological effects. The review highlights that ongoing advances in exosome engineering and the use of patient-derived vesicles may further enable translation to the clinic.
Key challenges remain for clinical development. Scalable production methods that preserve exosome integrity and functional cargo are needed for broader application. Cargo heterogeneity—variation in RNA and protein content among exosome preparations—poses hurdles for standardization and reproducibility. Regulatory considerations related to biologic classification, manufacturing control, and quality assurance will also influence clinical advancement. The review notes these obstacles while indicating that technological improvements and tailored manufacturing strategies are being pursued to address them.
Exosome-mediated siRNA delivery represents a biologically plausible and versatile platform for cancer gene silencing with multiple demonstrated preclinical benefits, including oncogene suppression, chemosensitization, and immunomodulation. Engineering solutions—surface functionalization, hybrid systems, and patient-derived exosomes—enhance targeting and payload performance. Early clinical data indicate safety and activity, but broader translation will require solutions for scalable manufacturing, reduction of cargo heterogeneity, and clear regulatory pathways. The review concludes that continued innovation in exosome engineering and rigorous translational efforts are poised to advance exosome-siRNA therapeutics in oncology.