mRNA therapeutics beyond vaccines: dosing precision challenges and clinical translation framework

Abstract

Messenger RNA (mRNA) therapeutics have emerged as a transformative platform following the success of COVID-19 vaccines. However, the transition from prophylactic vaccination to therapeutic protein replacement presents unique challenges, particularly in dosing precision and sustained protein expression control. This review examines the fundamental amplification effect where single mRNA molecules can produce 10³–10⁶ protein copies depending on construct optimization and cellular context, creating both therapeutic opportunities and dosing constraints that vary significantly across applications. Systematic analysis of peer-reviewed literature (2020–2025) and comprehensive clinical trial database examination reveal that current lipid nanoparticle delivery systems provide limited spatial and temporal control, with protein expression following predictable kinetics: rapid onset (2–6 hours), peak expression (24–48 hours), and exponential decline (7–14 days). Recent clinical evidence demonstrates exceptional efficacy in applications tolerating variable protein expression, including cancer immunotherapy where mRNA-4157 achieved a 44% reduction in recurrence risk versus pembrolizumab monotherapy (HR = 0.56, p < 0.05). However, significant constraints emerge for dose-sensitive applications requiring precise protein levels. Analysis of failure cases, including CureVac's CV9104 prostate cancer vaccine that failed to meet overall survival endpoints in Phase IIb trials, reveals critical design requirements for clinical success. Comparative analysis with AAV gene therapy demonstrates complementary therapeutic niches: mRNA excels in transient applications requiring temporal control, while AAV provides sustained expression for chronic conditions. Clinical translation requires careful selection of applications based on dosing tolerance, with cancer immunotherapy, infectious disease prevention, and transient protein therapies representing optimal use cases, while enzyme replacement therapy and hormone replacement face fundamental constraints with current platforms.