From CAR-T Cells to Exosome-Based Immunotherapy: Exploring the Frontiers of Cell-Free Targeted Cancer Therapeutics

Chimeric antigen receptor (CAR) cell therapies have revolutionized cancer immunotherapy by enabling targeted and potent antitumor immune responses. However, clinical challenges such as limited efficacy in solid tumors, severe toxicities including cytokine release syndrome (CRS), and manufacturing complexities restrict their broader use. Recently, CAR cell-derived exosomes (CAR-Exos) have emerged as promising cell-free therapeutic alternatives that retain the key antitumor functionalities of their parent cells while potentially overcoming the limitations of live cellular therapies. These nanoscale vesicles can deliver bioactive CAR molecules, cytotoxic proteins, and immunomodulatory cargo, enabling targeted tumor cell killing with reduced systemic toxicity and offering "off-the-shelf" applicability. This review comprehensively explores the biology, engineering, and therapeutic potential of CAR-Exos derived from T cells, natural killer (NK) cells, and other immune effectors. We discuss advances in isolation, characterization, and cargo profiling techniques, as well as preclinical and early clinical data supporting their application. Further, we address translational challenges including large-scale production, biodistribution, and immune evasion in tumor microenvironments. Combining cellular and exosomal CAR platforms holds promise to enhance efficacy and safety in cancer treatment, representing a frontier in targeted immunotherapy.