CAR-T cell-derived exosomes and cancer immunotherapy: advancing production and delivery through biofabrication.

Chimeric antigen receptor (CAR) T cell therapy has transformed the treatment of hematologic malignancies, but it still faces major barriers in solid tumors due to poor infiltration, an immunosuppressive microenvironment, and sometimes severe toxicities. CAR-T cell-derived exosomes (CAR-T-EXOs) have emerged as a potentially safer, more scalable acellular alternatives that preserve tumor-specific CAR recognition and cytotoxic functions while potentially reducing risks such as cytokine release syndrome and neurotoxicity. These nanosized vesicles can penetrate the dense tumor stroma and reprogram the immunosuppressive niches potentially more effectively than the cellular therapies. The recent advances in biofabrication are now enabling the high-yield production, functional validation, and more precise delivery of CAR-T-EXOs. The biofabricated models, including the three-dimensional spheroids, organoids, bioprinted constructs, and tumor-on-chip (ToC) systems, offer more physiologically relevant platforms for evaluating exosome trafficking and efficacy. Meanwhile, smart delivery systems such as stimuli-responsive hydrogels, nanofiber scaffolds, and hybrid nanovesicles provide spatiotemporal control over the exosome release. Despite all these promises, clinical translation is still hindered by the variability in isolation methods, characterization procedures, and regulatory frameworks. This review tries to integrate immunology, bioengineering, and translational perspectives to outline the biological advantages of the CAR-T-EXOs, to survey the latest biofabrication strategies, and to discuss the regulatory challenges. We also highlight some emerging paradigms, like exosome mimetics, nanorobotics, and personalized ToC testing, that are likely to speed up the next generation of safer and more effective exosome-based immunotherapies for solid tumors.