Engineering brain-penetrant PROTACs: Bridging molecular design and CNS delivery
Advanced Drug Delivery Reviews, vol. 234, pp. 115876
Abstract
The drug development for central nervous system (CNS) disorders, particularly neurodegenerative diseases, 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, a range of CNS-targeted delivery strategies have emerged, advancing PROTAC research toward more translatable therapeutic applications. 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.
Authors 22
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University of Nottingham · China Pharmaceutical University
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China; School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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University of Nottingham · China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Affiliation as printed
Department of Computer Science, RWTH Aachen University; Aachen 52074, Germany
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Chinese Academy of Sciences · Shanghai Institute of Materia Medica
Affiliation as printed
State Key Laboratory of Chemical Biology and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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Chinese Academy of Sciences · Shanghai Institute of Materia Medica
Affiliation as printed
State Key Laboratory of Chemical Biology and Center of Pharmaceutics, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Affiliation as printed
School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK
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University of Nottingham · China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Affiliation as printed
School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China. Electronic address: zaxu@chem.ecnu.edu.cn
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China Pharmaceutical University · State Key Laboratory of Natural Medicine
Affiliation as printed
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 211198, China
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Affiliation as printed
School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, UK. Electronic address: Zheying.Zhu@nottingham.ac.uk
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