Viral Platforms and Synthetic Nanoparticles in Transforming CAR-T Cell Therapy: A Review of Recent Experimental Advances in Enhancing Safety and Efficacy

Chimeric antigen receptor T-cell (CAR-T) therapy represents a transformative breakthrough in the treatment of hematological malignancies.However, its clinical efficacy against solid tumors is greatly hindered by physical stromal barriers and a complex, immunosuppressive tumor microenvironment (TME).In addition to these biological hurdles, the high cost of ex vivo manufacturing and the risk of severe adverse effects, such as cytokine release syndrome, limit widespread patient access.The aim of this review was to analyze reports published between 2020 and 2025 regarding the use of viral and synthetic nanoplatforms to improve the safety and efficacy of CAR-T therapy, with a particular focus on ex vivo cell engineering and innovative strategies for in vivo CAR-T cell generation.The review first evaluates how lipid-and polymer-based nanoparticles, acting as nonviral vectors, can revolutionize CAR-T engineering by providing cost-effective alternatives to viral transduction, accelerating cell preparation, and minimizing the risks associated with random genomic integration.It then examines the application of multifunctional nanocatalysts designed to enhance T-cell infiltration and actively modulate the TME to overcome immune evasion.Crucially, the review explores cutting-edge in vivo platforms, including VivoVec and adaptable chimeric antigen receptor T-cell (AdCAR-T) systems, which facilitate direct endogenous lymphocyte reprogramming, thus bypassing lymphodepletion and the logistical burdens of specialized laboratory processing.Integration of these nanotechnologies into such workflows enables the development of "smart," controllable therapeutic systems that improve both safety and scalability in personalized oncology.