Revitalizing Aged Immunity: mRNA-Based Thymic Signal Replacement

An MIT team reports an mRNA-based “thymic signal replacement” that restores thymic-like support and strengthens vaccine responses in aged preclinical models. The study describes targeted mRNA delivery to the liver to recreate thymic signals, with effects observed in aged animals.

Researchers transiently reprogrammed hepatocytes via intravenous synthetic mRNA encoding thymic-supportive factors, producing short-lived hepatic protein expression that circulates to T-cell progenitors. The liver was selected as an ectopic niche because it retains protein-production capacity with age and is accessible to lipid-nanoparticle uptake—features that favor scalability and reversibility. To date, results are limited to preclinical models.

Treated aged animals showed expanded, more diverse peripheral T-cell populations, improved T-cell functional markers, and stronger antigen-specific responses, including an increased vaccine response after immunization; the report also noted potential synergy with checkpoint-blockade cancer therapy.

Key translational challenges remain. Species differences in thymic biology and immune reconstitution may limit extrapolation from rodents to humans and require comparative studies; hepatic delivery, dosing, and safety concerns in older adults—particularly immune activation and off-target effects—necessitate focused preclinical toxicology. Regulatory and trial-design hurdles include defining geriatric-relevant endpoints and demonstrating durable clinical benefit in stepwise trials. Together these issues support staged clinical evaluation rather than immediate clinical adoption.