Photofabrication of fluorescent nanospheres from de novo designed peptides, and their enzyme-responsive dissociation in living cells

Abstract

Photochemical synthesis stands out as an exceptional approach for the bottom-up fabrication of functional assemblies using peptide building blocks. Incorporating a blend of noncovalent and covalent interactions, a series of peptide amphiphiles were designed de novo and synthesized to architect fluorescent nanospheres directly by means of photochemistry. Drawing from our established designs and experience, these peptide sequences were structurally encoded with photoactive tyrosine–tyrosine (YY) motifs at both termini, and the intervening spacer was filled with a specific Pro-Leu-Gly-Leu-Ala (PLGLA) segment and functional charge-bearing residues, including anionic D (aspartic acid), cationic R (arginine), and neutral X (ε-aminocaproic acid). The PLGLA segment acts as a stimuli-responsive element, enabling a targeted response to enzymatic matrix metalloproteinases (MMPs) in the tumor microenvironment (TME), while the charge-bearing residues serve as occupational units for drug hosting, balancing molecular amphiphilicity and regulating charge distribution. As anticipated, these functional nanospheres, efficiently constructed from encoded peptide strands upon exposure to light, were capable of hosting cationic RhB, anionic FL, and neutral DPA as fluorescent indicators, and responding to TME for MMP-responsive release of model drugs. This innovative strategy not only underlines the versatility of peptide-based assemblies but also showcases the potential of these nanospheres in targeted drug delivery and bioimaging applications.