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Engineering brain-penetrant PROTACs: Bridging molecular design and CNS delivery
Xinuo Li1, Jinran Li2, Yuan Sun2
1State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK.
Advanced Drug Delivery Reviews
|April 24, 2026
Summary
Proteolysis-targeting chimeras (PROTACs) show promise for neurodegenerative diseases but face blood-brain barrier challenges. Advances in delivery systems and molecular engineering are improving brain penetration for these novel CNS drugs.
Area of Science:
- Neuroscience
- Pharmacology
- Biotechnology
Background:
- Drug development for central nervous system (CNS) disorders, including neurodegenerative diseases (NDs), is challenging.
- Proteolysis-targeting chimeras (PROTACs) offer a novel therapeutic approach but struggle with blood-brain barrier (BBB) permeability and pharmacokinetics.
Purpose of the Study:
- To review recent advances and challenges in CNS-targeted delivery strategies for PROTACs.
- To highlight molecular engineering approaches enhancing PROTAC drug-likeness and BBB transport.
- To discuss future directions for PROTAC development in treating CNS disorders.
Main Methods:
- Review of noninvasive BBB-penetrant delivery systems (viral vectors, exosomes, nanocarriers, biomimetic vehicles).
- Emphasis on intranasal administration for direct brain delivery.
- Analysis of molecular engineering strategies (E3 ligase selection, linker modulation, ligand optimization).
Main Results:
- Diverse delivery strategies are emerging to improve PROTAC brain penetration.
- Molecular engineering enhances PROTAC properties for better CNS exposure.
- Current designs integrate peptides, nanoparticles, and prodrugs to optimize stability, selectivity, and brain exposure.
Conclusions:
- Integrating advanced delivery platforms with rational structural optimization is crucial for enhancing BBB permeability.
- Artificial intelligence and targeted protein degradation offer new pathways for targeting undruggable CNS proteins.
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