Plenary lecture given by Prof. Junbai Li (Chinese Academy of Sciences) at the XVII B-MRS Meeting, in Natal (Brazil), on September 17, 2018.

1. INSTITUTE OF CHEMISTRY CHINESE ACADEMY OF SCIENCE
中 国 科 学 院 化 学 研 究
所
Molecular Assembly of Peptide based Materials
towards Biomedical Application
Junbai Li
Institute of Chemistry
Chinese Academy of Sciences, Beijing

2. Institute of Chemistry, Chinese Academy of Sciences (CAS)
Research Characteristic
Multidisciplinary
Interdisciplinary
Comprehensive
Polymer
Chemistry
Green Printing
Advanced Polymer Material
Polymer Physics/Chemistry
Engineering Plastics
Analytical
Chemistry
Analytical Chemistry for
living biosystems
Physical
ChemistryColloid , Interface Sciences
Chemistry Thermodynamics
Molecular Nanostructure
Organic Solid
Reaction Dynamics
Organic
Chemistry
Molecular Recognition
Organic Solid
Photochemistry
Nanoscience
Molecular Nanostructure
Nanotechnology
Numbers of SCI Publication
SCI Citation ranks No. 1 in
Chinese institutions on Chemistry

3. Molecular Assembly
Self-assembly
Hydrogen bonds
Aromatic interactions
van der Waals interactions
……
Self-assembly
Electrostatic interactions
Hydrophobic interactions
Coordination interactions
……
Building Blocks
Supermolecular Assembly
Adler-Abramovich L, Gazit E. Chem. Soc. Rev. 2014, 43, 6881.

4. lipid
peptide
protein
Cell
cell membrane
microtubule
motor protein E. Coil
chloroplast
mitochondria
Organism contains various scales of hierarchical assembly structures
and relies on their collection to implement each process of life

5. Biomolecule-based Assemblies
Layer-by-layer (LbL) assembly LbL Assembled Micro/Nanostructures
and their biomedical applications
lipid peptide protein

6. Biomedical Application
LbL Assembled Micro/Nanostructures
Layer-by-layer (LbL) assembly
LbL Assembled Micro/Nanostructures
and their biomedical applications
Blood Substitutes
Drug Carriers

7. Biomolecule-based Complex Assemblies as
Artificial Cell Structure
pH or light-driven ATP BiosynthesisRotary Motor—ATPase
Linear Motor—Kinesin Kinesin-driven Cargo Delivery

8. Super Resolution Fluorescence Microscopy (STORM) to
Observe Biomolecule-based Complex Assemblies
Distribution of gelatin in CaCO3 crystal
Tubular compartments in NIH3T3 cellsInteraction between FF and liposomes
Interactions between the tube DNA origami and lysosomes

9. Angew. Chem. Int. Ed. 2018, 57, 1903
Angew. Chem. Int. Ed. 2018, 57, 7759
Angew. Chem. Int. Ed. 2018, 57, 6049
Angew. Chem. Int. Ed., 2018, 57, 11404
Angew. Chem. Int. Ed. 2018, 57, 6532
Angew. Chem. Int. Ed. 2017, 56, 12903
Angew. Chem. Int. Ed. 2017, 56, 2660
Angew. Chem. Int. Ed. 2016, 55, 13538
Angew. Chem. Int. Ed., 2016, 55, 908
Angew. Chem. Int. Ed. 2015, 54, 12782
Angew. Chem. Int. Ed. 2014, 53, 2366
Angew. Chem. Int. Ed. 2011, 50, 11186
Angew. Chem. Int. Ed. 2007, 46, 6996
Adv. Mater., 2016, 28, 1251
Adv. Mater., 2016, 28, 1302
Adv. Mater., 2016, 28, 1312
Chem. Rev. 2015, 115, 1597
Adv. Funct. Mater., 2018, 28, 1706557
Adv. Funct. Mater., 2016, 26, 2651
Adv. Funct. Mater. 2015, 25, 1193
Adv. Funct. Mater. 2012, 22, 2673
Adv. Funct. Mater. 2012, 22, 1446
ACS Nano, 2018, 12, 1445
ACS Nano 2018, 12, 1934
ACS Nano 2017, 11, 10489
ACS Nano, 2017, 11, 10175
ACS Nano, 2017, 11, 7349
ACS Nano, 2016, 10, 556
ACS Nano 2015, 9, 2689
ACS Nano 2014, 8, 8529
ACS Nano 2012, 6, 10910
ACS Nano 2012, 6, 6897
Representative Work

10. Biological inspired aromatic dipeptide (FF)
NH2-DAEFR HDSGY EVHHQ KLVFF AEDVG SNKGA IIGLM VGGVV IA-COOH
Alzheimer’s amyloid β-peptide motif: Aβ(1-42)
L-Phe-L-Phe(FF)
Amyloid Precursor
Protein (APP)
Aβ(1-42)
Reches, M., Gazit, E., Science 2003, 300, 625； C. H. Görbitz, Chem. Eur. J. 2001, 7,5153.
L-Phe-L-Phe(FF)
H2O

11. Peptide-based Molecular Assembly
Cation-diphenylalanine (CDP)
Diphenylalanine (FF)
Yan. et al., Chem. Soc. Rev., 39 (2010) 1877-1890

12. Cation-diphenylalanine (CDP)
Diphenylalanine (FF)
Glutaraldehyde (GA)
12
Glutaraldehyde (GA) mediated assembly of dipeptide
Schiff Base
-C=N-
Peptide-based Molecular Assembly
Y. Jia, J. Li*, Chem. Rev., 115 (2015) 1597

13. GA/FF Nanoparticles——Enzyme Carrier
water
pH=5.0 pH=6.5 pH=7.2 pH=8.1
The pH-triggered fast disassembly of FF nanoparticles

14. Adsorption of different small molecules into FF nanoparticles, and their
adsorption efficiency (AE) and loading efficiency (LE)
The release of ibuprofen (IBU)
Burst release within 5 s
Turbidity change
pH-responsive
UV–vis spectra
J. Fei, H. Zhang, A. Wang, C. Qin, H. Xue, J. Li*, Adv. Healthcare Mater. 2017, 6, 1601198

15. Thrombin-FF nanoparticles sprayed into different PBS solutions
in vitro clotting measurement using different sprays
J. Fei, H. Zhang, A. Wang, C. Qin, H. Xue, J. Li*, Adv. Healthcare Mater. 2017, 6, 1601198
in vivo clotting measurement using different sprays

16. GA/CDP Nanoparticles——Drug Carrier
Glutaraldehyde (GA) Cation-diphenylalanine (CDP)
H. Zhang, J. Fei, X. Yan,* A. Wang, J. Li*, Adv. Funct. Mater., 2015, 25, 1193
CDP Nanocarriers (CDPNCs)

17. CDPNCs co-incubated with trypsin in PBS
0 days
5 days
1 days
10 days
CDPNCs degraded in HeLa cells over time
Good Biodegradability of CDPNCs

18. The loading and release of DOX from CDPNCs
Drug release from CDP-DOX nanoparticles
Cytotoxicity of CDPNCs-DOX for HeLa cells
Gradually release
18
H. Zhang, J. Fei, X. Yan,* A. Wang, J. Li*, Adv. Funct. Mater., 2015, 25, 1193

19. Co-encapsulated two-photon fluorescent dye bis(pyrene) (BP) and
a photosensitizer rose bengal (RB) in CDP/GA nanoparticles 400 450 500 550 600 650 700
0
1000
2000
3000 BP-CDPNP
BP-CDPNP-RB
CDPNP-RB
Two-photonFL
Intensity
Wavelength/nm
Two-photon excitation fluorescence spectra
B. Sun, L. Wang, Q. Li, P. He, H. Liu, H. Wang, Y. Yang*, J. Li*, Biomacromolecules, 2017, 18, 3506-3513
450 500 550 600 650
0.0
0.4
0.8
1.2
RB
BP
Emission spectra of BP and absorption spectra of RB
Normalized
Intensity
Wavelength/nm
BP-GA/CDP-RB Nanoparticles

20. CDP/Genipin Nanospheres——Photodynamic Therapy
X. Yang, J. Fei, Q. Li, J. Li*, Chem. Eur. J., 2016, 22, 6477
Characterization of dipeptide-genipin
nanospheres (DPGNSs)
The assembly of dipeptide-genipin nanospheres and
their application as intrinsic photosensitizers in PDT

21. FTIR, UV/Vis spectra, fluorescence emission spectrum and
CLSM image of dipeptide-genipin nanospheres
The photosensitivity of nanospheres
Under irradiation, DPGNSs can generate 1O2 and therefore they could serve as a new
efficient intrinsic photosensitizer for PDT.

22. 3D-CLSM image of the MCF-7
cells endocytosing DPGNSs
Relative content of cellular ROS Cell viability with
increased concentrations of DPGNS
22
X. Yang, J. Fei, Q. Li, J. Li*, Chem. Eur. J., 2016, 22, 6477

23. 23
Optical Property of Peptide-based Assembly
C. Wu, Z. X. Wang, H. X. Lei, W. Zhang, Y. Duan,
J. Am. Chem. Soc. 2007, 129, 1225-1232
Cation-diphenylalanine (CDP)
CPABS
HPABS
MO
Sulfonic-azobenzene is the analog of Congo red,
which is an important medical molecule for the
detection and therapy of Alzheimer’s disease
Congo red

24. urchin-like structures flower-like structures plate-like structures

25. urchin-like
structures
CPABS
flower-like
structures
HPABS
plate-like
structures
MO
CDP
FTIR
XRD pattern
urchin-like structures
flower-like structures
plate-like structures
H. Ma, J. Fei, Y. Cui, J. Zhao, A. Wang, J. Li*, Chem. Commun., 2013, 49, 9956

26. urchin-like structures
flower-like structures
plate-like structures
H. Ma, J. Fei, Y. Cui, J. Zhao, A. Wang, J. Li*, Chem. Commun., 2013, 49, 9956
increasing the amount of CDP would induce morphology change
26

27. UV
Vis
Cation-diphenylalanine (CDP)
Photoswitchable
sulfonicazobenzene to
optically manipulate the
self-assembly of CDP
Photo-induced reversible structural transition of CDP self-assembly
H. Ma , J. Fei , Q. Li , J. Li *, Small, 2015, 11, 1787-1791

28. branched nanostructures
with elongated nanoplates and helical nanobelts
trans-cis isomerization

29. trans
cis
photo-induced structural transition
H. Ma , J. Fei , Q. Li , J. Li *, Small, 2015, 11, 1787-1791

30. X. Liu, et al., Angew Chem. Int. Ed. 2017, 56, 2660
The transition of a dipeptide-based organogel into a
hexagonal crystal under extremely cold conditions (77 K)
SEM images of FF–toluene organogels after
different numbers of cryogenic treatments

31. Cross-polarized microscopy images of the
assembly at different angles
Photoluminescence emission spectra of FF
solution and FF–toluene gel
at room temperature.
after cryogenic treatment
X. Liu, J. Fei, A. Wang, W. Cui, P. Zhu, J. Li*, Angew Chem. Int. Ed. 2017, 56, 2660

32. The self-assembly of FF crystals from molecules in NH4OH solution
withdrawal speed of 2.0 μm/s
withdrawal speed of 4.6 μm/s
Self-Assembly of Ultralong Aligned Dipeptide Single Crystals

33. FF single crystal imaged in
reflection with crossed polarizersCharacterization of the FF single crystals
B. Sun, Q. Li, H. Riegler, S. Eickelmann, L. Dai, Y. Yang, R. Perez-Garcia, Y. Jia, G. Chen,
J. Fei, K. Holmberg, J. Li*, ACS Nano, 2017, 11, 10489

34. Solubility of FF
pH
The change of concentration of FF (CFF) in the
NH OH solution as NH and H O evaporate.
Aligned FF single crystals formed under different
NH4OH concentration and temperature
38 oC，0.1% 75 oC，0.1%
75 oC，28%75 oC，5%
The “gradient single crystals” at a silicon wafer (positions
1,2,3,4) obtained with different withdrawal speeds
2.0 μm/s
2.0 μm/s
4.6 μm/s
4.6 μm/s

35. Proposed assembly mechanism of the aligned FF single crystal growth process
35
B. Sun, Q. Li, H. Riegler, S. Eickelmann, L. Dai, Y. Yang, R. Perez-Garcia, Y. Jia, G. Chen,
J. Fei, K. Holmberg, J. Li*, ACS Nano, 2017, 11, 10489

36. Optical waveguide properties of aligned FF single crystals
5 µm
Optical waveguiding property
B. Sun, Q. Li, H. Riegler, S. Eickelmann, L. Dai, Y. Yang, R. Perez-Garcia, Y. Jia, G. Chen,
J. Fei, K. Holmberg, J. Li*, ACS Nano, 2017, 11, 10489

37. GA/FF crystalline platelet——Active Optical Waveguiding
X. Yan, Y. Su, J. Li ,* J. Früh, H. Möhwald,, Angew. Chem. Int. Ed., 2011, 50, 11186
toluene solution

38. Optical Waveguiding of Peptide Crystals

39. Optical Waveguiding of Peptide Crystals

40. K. Tao, et al., Nature Comm. 2018 in press
Optical Waveguiding of Peptide Crystals

41. Conclusions
1. Taking dipeptide diphenylalanine and its derivatives as building block, we have
constructed a series of assemblies with 1D, 2D and 3D structures via molecular
assembly.
2. Controlled assembly and disassembly of diphenylalanine peptides can be easily
tuned by changing physicochemical parameters or assembly conditions, such as
concentration, solvents and introducing small molecules to assembly systems.
3. These peptide-based assemblies possess good biodegradability, pH-responsivity
and physiological environment-responsivity, thus they may be potentially applied
in drug carriers, fast blood clotting and other biomedical applications.
4. The peptide-based fibrils possess good crystalline structures and demonstrate
excellent optical properties, they may be potentially applied in optical waveguiding.

42. Acknowledgements
 Contributors：
Q. LiH. Zhang X. K. Yang X. C. Liu
W. G. Dong J. L. Li
Y. Jia
J. R. Xia
J. B. Fei
G. L. Li
H. C. Ma
X. B. LiT. T. YuanB. B. Sun
￥￥￥￥￥：