Non-viral gene delivery offers a promising route for treating central nervous system (CNS) disorders, but its translation remains limited by the difficulty of achieving both safety and efficiency in the brain. This review summarizes recent advances in non-viral CNS gene delivery from the perspectives of safety and efficacy, highlighting progress in biodegradable and biomimetic materials, cargo engineering, blood-brain barrier (BBB)-crossing strategies, administration route optimization, and cell-type-specific targeting. We further discuss representative clinical studies. Overall, this review emphasizes that the future of non-viral CNS gene therapy will depend on the rational co-optimization of safety and efficacy.