mRNA nanodelivery systems: targeting strategies and administration routes.

With the great success of coronavirus disease (COVID-19) messenger ribonucleic acid (mRNA) vaccines, mRNA therapeutics have gained significant momentum for the prevention and treatment of various refractory diseases. To function efficiently in vivo and overcome clinical limitations, mRNA demands safe and stable vectors and a reasonable administration route, bypassing multiple biological barriers and achieving organ-specific targeted delivery of mRNA. Nanoparticle (NP)-based delivery systems representing leading vector approaches ensure the successful intracellular delivery of mRNA to the target organ. In this review, chemical modifications of mRNA and various types of advanced mRNA NPs, including lipid NPs and polymers are summarized. The importance of passive targeting, especially endogenous targeting, and active targeting in mRNA nano-delivery is emphasized, and different cellular endocytic mechanisms are discussed. Most importantly, based on the above content and the physiological structure characteristics of various organs in vivo, the design strategies of mRNA NPs targeting different organs and cells are classified and discussed. Furthermore, the influence of administration routes on targeting design is highlighted. Finally, an outlook on the remaining challenges and future development toward mRNA targeted therapies and precision medicine is provided.