This review summarizes advances and persistent challenges in engineering and delivering PROTACs to the CNS — covering BBB-penetrant formulations (viral vectors, exosomes, nanoparticles, intranasal routes) and molecular optimization (E3 ligase choice, linker properties, CPPs, prodrugs) to improve…

By outlining practical delivery platforms and rational design levers to get targeted degraders into the brain, the paper provides actionable direction for developing PROTAC strategies against Parkinson's-relevant, otherwise hard-to-drug targets such as alpha-synuclein and other neurodegeneration…

The drug development for central nervous system (CNS) disorders, particularly neurodegenerative diseases (NDs), such as Alzheimer's disease, Parkinson's disease, and Huntington's disease, faces formidable challenges. While proteolysis-targeting chimeras (PROTACs) represent a paradigm-shifting modality by redefining target engagement mechanisms, their clinical translation remains hindered by limited blood-brain barrier (BBB) permeability and suboptimal pharmacokinetic profiles. In recent years, diverse CNS-targeted delivery strategies have emerged, driving PROTAC research toward translatable therapeutic potential. This Review highlights recent advances and persistent challenges in noninvasive BBB-penetrant delivery systems, including viral vectors, engineered exosomes, functionalized nanocarriers, and cell membrane-derived biomimetic vehicles, with a particular emphasis on intranasal administration as a direct route to the brain. Parallel progress in rational molecular engineering, encompassing E3 ligase selection, linker polarity and rigidity modulation, and optimization of target-binding ligands, has further enhanced PROTAC drug-likeness and BBB transport efficiency. Current CNS-directed PROTAC designs increasingly incorporate cell-penetrating peptides, nanoparticles, and prodrug formulations to balance stability, selectivity, and brain exposure. Future advanced PROTAC delivery platforms require integrating multifunctional nanocarriers with rational structural optimization to enhance BBB permeability. Further artificial intelligence-accelerated molecular design and targeted protein degradation technologies offer novel avenues for addressing undruggable CNS targets.