Significant Progress in Nucleic Acid Brain-Targeting Nanocarrier System

On October 10th, Beijing Time, a new paper published on Nature Communications (https://www.nature.com/ncomms/), “Crossing the blood-brain-barrier with nanoligand drug carriers self-assembled from a phage display peptide”, presented the latest achievements in peptide-based brain-specific targeting nanocarrier system done by WU Linping’s group at Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences (GIBH-CAS), in collaboration with Prof. Moein Moghimi’s research team at Newcastle University, Britain. To overcome weak target-binding of nanoparticles functionalized with phage display peptides or cell-penetrating peptides, brain-targeting peptide was identified using phage display technology and its self-assembly into nanostructure was achieved through chemical modification of the peptide. The blood-brain-barrier (BBB) crossing mechanism of nanocarriers self-assembled from the peptide was further investigated. Subsequently, functional siRNA was successfully delivered into the brain as a result of improved efficacy and specificity in active targeting with nanoparticles bearing peptides. Such system provides a potential technical platform for intravenous administration of separate or combined small molecule, peptide, and nucleic acid-based drugs to cross the BBB into the brain, opening opportunities for modern therapy and gene medication in treating neural degenerative disorders. 

Nanoparicles as drug carriers have aroused wide attention for site-specific targeting of diagnostic and drug delivery for detection, monitoring and treatment of various diseases. A dominant strategy in targeting with drug carriers is their surface functionalisation with a wide range of target-specific ligands (e.g., folate, antibodies and their fragments, proteins such as transferrin and a plethora of designer peptides), a process often referred to as “active targeting”. The phage display technology is a valuable tool in identification of numerous peptide ligands for active targeting. The filamentous bacteriophage fd bind a cell target with exquisite specificity through its few copies of display peptides, whereas nanoparticles functionalized with hundreds to thousands of synthetically generated phage display peptides exhibit variable and often-weak target binding. WU Lingping’s group hypothesized that some phage peptides in a hierarchical structure rather than in monomeric form recognise and bind their target. To confirm this hypothesis, the authors focused on the brain-targeting peptide, GYR, as the key to breaking through. Tens of thousands of candidate drugs have been developed in the purpose of treating brain diseases, yet 98% of small-molecule drugs and almost all macromolecular drugs are not able to cross the BBB into the brain, which has become a major obstacle to treatment of brain disorders. Therefore it is demanded that nanocarrier system capable of crossing the BBB with high efficacy and specificity in brain-targeting is developed, to improve the therapeutic strategy for treating brain diseases. GYR peptide is a 15-amino acid peptide displayed by the filamentous phage fd clones, which shows high binding specificity to human brain capillary endothelial hCMEC/D3 cells in vitro and mouse brain endothelium in vivo. However, liposomes bearing GYR lack brain specificity. To overcome such drawback, GYR was rendered amiphiphilic through chemical modification and its self-assembly behavior can thus be controlled. GYR peptide with chemical modification can self-assemble into core-shell nanoparticles and multiple crossed β-sheet nanofibrils (or NanoLigand Carriers (NLCs) for short). 

The present study demonstrated that hierarchial forms of a brain specific phage-derived peptide target cerebral endothelial cells through transferrin receptor and the receptor for advanced glycation-end products (RAGE), cross the mouse blood-brain-barrier with high efficiency and reach neurons and microglial cells. More importantly, NLCs can be loaded with β-secretase 1  (BACE1)-specific siRNA complexes (BACE1 has been widely considered as an important target for treatment of Alzheimer’s disease since it is the key enzyme responsible for initiating Aβ generation, of which over accumulation is the typical pathological feature of the disease) and results showed effective down regulation of BACE1 expression on intravenous injection into mouse brain. No toxicity or inflammation induced by the system was revealed. In all, NLCs developed in this study as a safe and multifunctional nanocarrier realized active targeting through self-assembly of the chemically-modified peptide ligand into targetable nanocarriers, thus overcame efficacy and specificity limitation in active targeting with nanoparticles bearing phage display peptides, providing new technical and theoretical basis for future study on clinical transformation of brain targeting delivery of central nervous system medication. 

Principle Investigator WU Linping and Prof. Moein Moghmi are corresponding authors. The study received financial support by National Project of Major Research and Development of New Drug, Guangzhou Science and Technology Development Program, etc.   

The article can be found at https://www.nature.com/articles/s41467-019-12554-2.