In nature, numerous biological structures with distinct shapes are generated through self-assembly. Unlike spherical particles, biological nanofilaments such as microtubules and collagen leverage their specificity and multivalent binding capabilities to perform unique biological functions. However, the interactions between nanofilaments and biomolecules remain unclear, and their unique behaviors are poorly understood.

In a study published in Advanced Materials on November 28, a research team led by Professor LI Yaping from Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, Professor ZHANG Pengcheng from ShanghaiTech University, and Professor ZHANG Lu from Fujian Institute of Research on the Structure of Matter of the Chinese Academy of Sciences, jointly constructed peptide-based nanofilaments (PFs) formed by self-assembling peptide amphiphiles (PAs). Nonspecific protein adsorption of PFs was reduced by regulating their conformation, thereby altering their in vivo biological behavior and improving the efficiency of anticancer drug delivery.

In this study, researchers reported a set of nanofilaments composed of unique PAs that share a common palmitoylated β-sheet forming segment (C16-GVVQQ) and headgroup (HKD) with their parental PA (P1, C16-GVVQQHKD). The nanofilaments were further modified with different homotetrapeptidic inserts (glycine, serine, proline, and hydroxyproline), forming P2-P5. Cryo-transmission electron microscopy illustrated the formation of self-assembling PFs. By changing homotetrapeptide, researchers imposed different conformations within PFs, resulting in notable variations in the density of intermolecular hydrogen bonds, thereby determining the extent of protein adsorption. The adsorbed proteins further induced different degrees and patterns of interfilament entanglement of PFs, affecting biological fates of PFs.

Among these PFs, P5Fs with tetrahydroxyproline segment exhibited the lowest intermolecular hydrogen bond density and the lowest composition of β-sheet secondary structure. As a result, P5Fs showed the least nonspecific protein adsorption and the smallest degree of interfilament entanglement. In vivo, P5Fs improved circulation, biodistribution, and antitumor efficacy of both physically encapsulated and chemically conjugated drugs.

These findings will deepen the understanding of nanofilament-protein interactions and filament-filament interactions, facilitating rational design of nanofilaments through peptide conformation control for chemical engineering and anticancer drug delivery.

DOI: 10.1002/adma.202409130

Link: https://doi.org/10.1002/adma.202409130

Biological fates of nanofilaments with different designs. (Image byCAI Ying)

Contact:

JIANG Qingling

Shanghai Institute of Materia Medica, Chinese Academy of Sciences

E-mail: qljiang@stimes.cn