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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.

Keywords:

Blood-brain barrier Delivery platforms Molecular design Neurodegenerative diseases Proteolysis-targeting chimeras

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Published on: May 15, 2019

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.