mRNA nanotherapeutics for sepsis: immune modulation strategies and translational challenges

Sepsis remains a major global health burden and is characterized by a dysregulated host immune response that evolves from early hyperinflammation to late-stage immunosuppression. Despite advances in supportive care, effective pharmacological therapies capable of modulating this dynamic immune landscape are still lacking. Messenger RNA (mRNA)-based therapeutics have emerged as a promising approach due to their ability to enable transient, controllable expression of immunomodulatory proteins; however, their clinical translation is hindered by intrinsic instability, rapid degradation, and inefficient tissue delivery.

Nanotechnology offers innovative solutions to overcome these limitations by improving mRNA protection, cellular uptake, and targeted delivery. A variety of nanocarriers, including lipid nanoparticles, polymeric systems, inorganic nanomaterials, and biomimetic vectors, have been developed for mRNA delivery in sepsis. Emerging strategies incorporating macrophage-targeting ligands and stimuli-responsive release mechanisms further enhance delivery precision and therapeutic efficacy. Preclinical studies demonstrate that mRNA-based nanotherapeutics can suppress cytokine storms, restore immune function, and attenuate organ injury in experimental models of sepsis.

This review summarizes recent advances in mRNA-based nanotherapeutics for sepsis, with a focus on delivery strategies, immunomodulatory mechanisms, and translational potential. Key challenges related to delivery efficiency, safety, and regulatory considerations are discussed. Finally, future directions are proposed for the development of individualized, stage-specific mRNA nanotherapies aimed at restoring immune homeostasis in critically ill patients.