<p>As evidenced by the seven U.S. Food and Drug Administration (FDA)-approved products, chimeric antigen receptor (CAR)-T cell therapy has gained unprecedented success in cancer treatment, particularly in blood cancers. Nonetheless, despite these impressive results, CAR-T cell therapy is a complex and challenging procedure with several hurdles that reduce its affordability and accessibility. These issues include time-consuming and labor-intensive ex vivo manufacturing, safety concerns regarding the viral-based gene delivery, and limited in vivo persistence and function. In recent years, nanoparticles (NPs) have been introduced as versatile tools with the potential to overcome these limitations and improve the efficacy and safety profile of CAR-T cells. Given the lack of a comprehensive analysis of the transformative potential of the use of NPs in CAR-T cell therapy and the roadblocks to their clinical translation in current literature, this review aims to provide a comprehensive and critical overview of NP-based strategies in CAR-T cell therapy, focusing on three key applications: production of CAR-T cells using a fully non-viral approach, enhancing the in vivo persistence and function of CAR-T cells, and in vivo generation and genome editing of CAR-T cells to circumvent the laborious ex vivo cell engineering and expansion stages. We explore the comparative advantages of different types of NPs (e.g., lipid-based and polymeric NPs) and discuss various approaches for optimizing NP design to address manufacturing and regulatory barriers. Finally, to provide a holistic view of the current state and future opportunities in these emerging fields, various roadblocks to their clinical translation (such as safety, scalability, and regulatory hurdles) and potential solutions are discussed. By exploring preclinical innovations and their clinical applicability, this review can guide future research toward scalable, efficient, and safe NP-assisted CAR-T cell therapy.</p>