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.