Viral vectors have long been central to cancer immunotherapy, particularly for ex vivo chimeric antigen receptor (CAR)-T cell engineering and cancer vaccine development. Despite their success, clinical translation remains limited by immunogenicity, insertional mutagenesis, restricted cargo capacity, and high production costs. These drawbacks not only compromise safety but also hinder scalability and repeated dosing, both of which are critical for durable cancer control. To overcome these barriers, non-viral nanocarrier systems have emerged as versatile and safer alternatives. Lipid nanoparticles, polymeric platforms, biomimetic exosome-like vesicles, and hydrogel-based systems enable targeted and controlled delivery of nucleic acids, immunomodulators, and chemotherapeutics with enhanced stability, reduced systemic toxicity, and improved biocompatibility. Beyond passive delivery, these smart nanocarriers can be engineered with tumor-targeting ligands, immune checkpoint modulators, or stimulus-responsive release mechanisms to reprogram the tumor microenvironment and potentiate T-cell and dendritic cell activation. Furthermore, the modularity of nanotechnology facilitates co-delivery of multiple therapeutic agents, including antigens, adjuvants, and checkpoint inhibitors, allowing synergistic immunotherapeutic outcomes. Recent advances in large-scale manufacturing and clinical translation of lipid nanoparticle-based mRNA vaccines underscore the feasibility of these systems for oncology applications. As cancer immunotherapy evolves toward personalization and combination regimens, nanobiotechnology offers a transformative platform to replace conventional viral vectors, advancing safer, more effective, and clinically scalable treatments.
