Designed nanocage displaying ligand-specific Peptide bunches for high affinity and biological activity.
Protein-cage nanoparticles are promising multifunctional platforms for targeted delivery of imaging and therapeutic agents owing to their biocompatibility, biodegradability, and low toxicity. The major advantage of protein-cage nanoparticles is the ability to decorate their surfaces with multiple functionalities through genetic and chemical modification to achieve desired properties for therapeutic and/or diagnostic purposes. Specific peptides identified by phage display can be genetically fused onto the surface of cage proteins to promote the association of nanoparticles with a particular cell type or tissue. Upon symmetrical assembly of the cage, peptides are clustered on the surface of the cage protein in bunches. The resulting PBNC (peptide bunches on nanocage) offers the potential of synergistically increasing the avidity of the peptide ligands, thereby enhancing their blocking ability for therapeutic purposes. Here, we demonstrated a proof-of-principle of PBNCs, fusing the interleukin-4 receptor (IL-4R)-targeting peptide, AP-1, identified previously by phage display, with ferritin-L-chain (FTL), which undergoes 24-subunit assembly to form highly stable AP-1-containing nanocage proteins (AP1-PBNCs). AP1-PBNCs bound specifically to the IL-4R-expressing cell line, A549, and their binding and internalization were specifically blocked by anti-IL-4R antibody. AP1-PBNCs exhibited dramatically enhanced binding avidity to IL-4R compared with AP-1 peptide, measured by surface plasmon resonance spectroscopy. Furthermore, treatment with AP1-PBNCs in a murine model of experimental asthma diminished airway hyper-responsiveness and eosinophilic airway inflammation along with decreased mucus hyperproduction. These findings hold great promise for the application of various PBNCs with ligand-specific peptides in therapeutics for different diseases, such as cancer.
Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University , Daegu 700-422, Republic of Korea.
Jae Og
JO
Jeon
Soyoun
S
Kim
Eunsu
E
Choi
Kihyuk
K
Shin
Kiweon
K
Cha
In-Seop
IS
So
Sun-Ji
SJ
Kim
Eunsung
E
Jun
Dohee
D
Kim
Hyung Jun
HJ
Ahn
Byung-Heon
BH
Lee
Seung-Hyo
SH
Lee
In-San
IS
Kim
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage / Q000138:chemical synthesis / Q000276:immunology; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology*; D045744:Cell Line, Tumor; D015195:Drug Design; D005260:Female; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D053769:Nanocapsules / Q000008:administration & dosage* / Q000737:chemistry* / Q000648:ultrastructure; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology*; D011485:Protein Binding; D019948:Receptors, Interleukin-4 / Q000276:immunology*; D016896:Treatment Outcome
C513345:AP1 peptide; D018927:Anti-Asthmatic Agents; D053769:Nanocapsules; D010455:Peptides; D019948:Receptors, Interleukin-4