<p>Messenger RNA-based therapeutics have been successful in preventing and treating various diseases. Nonetheless, these therapies still face difficulties in achieving specific delivery to organs, tissues and cells, which are exacerbated by the need to overcome multilevel biological barriers and intrinsically complex physiological disease characteristics. Several approaches are being developed to overcome these challenges, including optimizing administration routes, enhancing targeting abilities and facilitating responsive release. These tailored design strategies have been utilized in applications including mRNA vaccines, protein replacement and gene editing for enhanced precision therapies. This Review discusses various heterogeneous barriers for mRNA delivery and nanocarrier-mediated mRNA precision-delivery strategies, and highlights their uses in biomedical applications. Moreover, we discuss current limitations and future perspectives to accelerate the development of precision mRNA delivery to address current clinical needs.</p>