Engineering age-adaptive mRNA lipid nanoparticle cancer vaccines via reprogramming systemic gene expression

Area of Science:

• Immunology
• Vaccinology
• Gerontology

Background:

• Lipid nanoparticle (LNP)-based mRNA vaccines are crucial for cancer immunotherapy.
• Efficacy in older individuals, a key demographic for cancer, is not well understood.
• Aging may impair vaccine performance, necessitating age-specific strategies.

Purpose of the Study:

• Investigate age-related barriers to mRNA LNP cancer vaccine efficacy.
• Identify mechanisms behind reduced vaccine performance in aged hosts.
• Develop strategies to enhance vaccine efficacy in older individuals.

Main Methods:

• Utilized SM-102 mRNA LNPs in aged and young mouse models.
• Assessed local and systemic transgene expression, immune cell responses, and tumor control.
• Performed transcriptomic profiling of immune cells.
• Engineered LNP formulations to improve distal antigen expression.

Main Results:

• Aged hosts exhibit markedly reduced systemic transgene expression in peripheral organs.
• Local immune responses remain largely intact, but systemic expression deficits limit T cell responses and tumor control.
• Impaired systemic mRNA translation is linked to downstream immune defects and reduced efficacy.
• A rationally selected LNP formulation restored distal antigen expression and T cell immunity in aged mice.

Conclusions:

• Systemic transgene expression is a critical, age-dependent factor in mRNA LNP cancer vaccine efficacy.
• Optimizing LNP formulations to sustain systemic expression can overcome age-related deficits.
• This approach enables the development of age-adaptive mRNA vaccines for cancer and aging-related diseases.