Brain-targeted delivery of messenger RNA drugs: Overcoming barriers and accelerating therapeutic breakthroughs

Messenger RNA (mRNA) therapeutics have emerged as a transformative platform with applications in cancer immunotherapy, infectious diseases, and genetic disorders. Their potential for central nervous system (CNS) diseases is promising due to programmable protein expression. However, effective delivery to the brain remains a major challenge, limited by mRNA instability and the restrictive blood–brain barrier (BBB). This review summarizes the fundamental features and therapeutic mechanisms of mRNA, analyzes key obstacles in CNS delivery, and discusses invasive and noninvasive administration routes, including intracerebroventricular, intrathecal, intravenous, intranasal, and ultrasound-assisted strategies. Emphasis is placed on emerging delivery systems such as lipid nanoparticles, polymeric and inorganic nanocarriers, exosomes, and biomimetic vesicles, focusing on their BBB-crossing mechanisms and in vivo efficacy. Finally, the review highlights recent advances and future directions in designing efficient, safe, and translatable mRNA delivery systems for CNS therapeutics, aiming to accelerate clinical translation of mRNA-based interventions for neurological diseases.