Immune memory engineering in mRNA therapeutics.

Messenger RNA (mRNA) therapeutics have revolutionized vaccine development and are rapidly expanding into cancer immunotherapy, infectious diseases, regenerative medicine, and protein replacement therapies. While considerable efforts have focused on maximizing antigen expression and short term immune responses, durable therapeutic efficacy ultimately depends on the establishment of long lasting immune memory. Emerging evidence suggests that immune memory is not merely a passive consequence of antigen expression but can be actively shaped through the rational engineering of antigen persistence, delivery, and immune programming. In this review, we propose immune memory engineering as a unifying framework for mRNA therapeutics that achieve durable immune protection. We examine three interconnected biological determinants of immune memory, including antigen persistence, antigen trafficking, and innate and spatial programming, and discuss how LNP engineering, formulation parameters, and tissue specific delivery quantitatively influence memory formation. We further highlight how artificial intelligence and multiomics approaches can integrate these determinants into predictive design strategies for optimizing durable immune responses. Together, these advances position immune memory engineering as an emerging design paradigm for developing next generation mRNA therapeutics with durable, controllable, and increasingly personalized immune protection.