The success of messenger ribonucleic acid (mRNA) vaccines has positioned them as a versatile and safe alternative to traditional protein-based therapeutics, enabling in situ protein production with a high efficiency. Intratumoral (i.t.) administration of therapeutic mRNA represents a critical strategy, allowing direct targeting of the tumor microenvironment (TME) while minimizing systemic drug exposure. This localized approach aims to convert immunosuppressive “cold” tumors into pro-inflammatory “hot” environments, consequently facilitating the in situ fabrication and release of proteins such as tumor-associated antigens and immunomodulatory proteins. This process not only initiates a potent local immune response but also can lead to systemic immunity against metastatic tumors, an immunological effect known as the “abscopal effect”. However, the physically dense, immunosuppressive TME presents significant challenges, including a low infiltration of immune cells, mRNA instability, poor cellular uptake, limited tissue penetration, and rapid clearance. To overcome these solid tumor barriers, nanotechnology platforms are indispensable. This review comprehensively examines the design and preclinical efficacy of various nanotechnology-based i.t. mRNA delivery systems for cancer immunotherapy. We discuss current challenges in clinical translation and provide future perspectives on advancing this promising field of cancer immunotherapy.
Ishikawa et al. (Thu,) studied this question.