CAR-T Cell-Derived Exosomes and Cancer Immunotherapy: Advancing Production and Delivery Through Biofabrication.

Abstract

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of hematologic malignancies, but it still faces some major barriers in solid tumors because of poor infiltration, the immunosuppressive microenvironment, and sometimes severe toxicities. The CAR-T cellderived exosomes (CAR-T-EXOs) have been emerging as safer and more scalable acellular alternatives that can preserve the tumor-specific CAR recognition and cytotoxic effect or functions, while avoiding the cytokine release syndrome (CRS) and neurotoxicity issues. These nanosized vesicles can penetrate the dense tumor stroma and reprogram the immunosuppressive niches 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 (3D) spheroids, organoids, bioprinted constructs, and tumor-on-chip 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 this promise, the clinical translation is still hindered by the variability in isolation methods, characterization procedures, and the 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 tumor-on-chip testing, that are likely to speed up the next generation of safer and more effective exosome-based immunotherapies for solid tumors.