Framework Nucleic Acid Nanomaterials for Central Nervous System Therapies: Design for Barrier Penetration, Targeted Delivery, Cellular Uptake, and Endosomal Escape

Therapeutic development for central nervous system (CNS) disorders remains hindered by inefficient drug penetration across the blood-brain barrier (BBB) and a lack of spatiotemporal precision targeting. Conventional nanocarriers face challenges such as structural heterogeneity, off-target effects, and limited BBB traversal, compromising clinical efficacy. Framework nucleic acid (FNA) nanomaterials, characterized by atomic-level precision, programmable self-assembly, and inherent biocompatibility, present a transformative platform to overcome these barriers. However, a systematic analysis of their design principles and therapeutic potential remains unexplored. This review systematically analyzes FNA design strategies for CNS applications, emphasizing four pivotal stages: BBB penetration, brain region/cell-specific targeting, enhanced cellular uptake, and subsequent endosomal/lysosomal escape for therapeutic cargo release. While preclinical studies highlight FNAs' potential in treating brain tumors, neurodegenerative diseases, ischemic stroke, clinical translation requires addressing biological stability, mechanistic clarity, and long-term biosafety. Integrating innovative design strategies, computational modeling, single-cell omics, and advanced 3D BBB models will accelerate the development of precision FNA-based therapies. By bridging precision nanodesign with neurobiological insights, this work provides actionable guidelines for advancing FNAs as paradigm-shifting tools for overcoming CNS therapeutic bottlenecks and accelerating their clinical translation.