Conformation Influences Biological Fates of Peptide‐Based Nanofilaments by Modulating Protein Adsorption and Interfilament Entanglement

Abstract Filamentous structures exert biological functions mediated by multivalent interactions with their counterparts in sharp contrast with spherical ones. The physicochemical properties and unique behaviors of nanofilaments that are associated with multivalent interaction with protein are poorly understood. Here, peptide‐based nanofilaments containing different homotetrapeptidic inserts are reported and their protein adsorption and biological fates are tested. By altering the homotetrapeptides, different peptidic conformations are imposed within the nanofilaments, which result in notable differences in the density of the intermolecular hydrogen bond, determining the amount of adsorbed proteins. The adsorbed proteins can further induce interfilament entanglement of different degrees and patterns, which influences biodistribution and phagocytosis. The nanofilaments with tetrahydroxyproline segment exhibit diminish interfilament entanglement, phagocytosis, and improve circulation, biodistribution, and antitumor efficacy. These findings can deepen the understanding of nanofilament‐protein interactions and filament‐filament interactions as in the case of amyloid‐β plaque, and facilitate the rational design of nanofilaments through peptide conformation control for chemical engineering and anticancer drug delivery.