Spatiotemporal control of chemical assembly in living cells remains challenging. We have now developed an efficient and general platform to precisely control the formation of assemblies in living cells. We introduced an O‐[bis(dimethylamino)phosphono]tyrosine protection strategy in the self‐assembly motif as the Trojan horse, whereby the programmed precursors resist hydrolysis by phosphatases on and inside cells because the unmasking of the enzymatic cleavage site occurs selectively in the acidic environment of lysosomes. After demonstrating the multistage self‐assembly processes in vitro by liquid chromatography/mass spectrometry (LC‐MS), cryogenic electron microscopy (Cryo‐EM), and circular dichroism (CD), we investigated the formation of site‐specific self‐assembly in living cells using confocal laser scanning microscopy (CLSM), LC‐MS, and biological electron microscopy (Bio‐EM). Controlling chemical assembly in living systems spatiotemporally may have applications in supramolecular chemistry, materials science, synthetic biology, and chemical biology.
Supramolecular chirality plays an indispensable role in living and synthetic systems. However, the generation and control of filament chirality in the supramolecular hydrogel of short peptides remains challenging. In this work, as the first example, we report that the heterodimerization of the enantiomeric mixture controls the alignment, chirality, and stiffness of fibrous hydrogels formed by aromatic building blocks. The properties of the resulting racemic hydrogel could not be achieved by either pure enantiomer. Cryo-EM images indicate that the mixture of L and D enantiomers forms chiral nanofibers, the percentage of which can be readily controlled through stoichiometric co-assembly of heterochiral enantiomers. 2D NOESY NMR and diffusion-ordered NMR spectroscopy reveal that heterodimerization of enantiomers plays a crucial role in the formation of chiral nanofibers. Further mechanistic studies unravel the mechanism of supramolecular chirality formation in this two-component system. Molecular dynamics simulations confirm that the intermolecular hydrogen bond and π–π interaction of heterodimers play important roles in forming a chiral hydrogel. Furthermore, regulation of the adhesion and morphology of mammalian cells is achieved by tuning the relative ratio of L and D enantiomers at the same concentration. This work illustrates a novel strategy to control the supramolecular chirality of aromatic peptide hydrogels for materials science.
Graphical Abstract
Pharmaceutical science based on biological nanotechnology is developing
rapidly in parallel with the development of nanomaterials and nanotechnology
in general. Pectin is a natural polysaccharide obtainable from a wide
range of sources. Here, we show that doxorubicin (DOX)-conjugated
hydrophilic pectin (PET) comprising an amphiphilic polymer loaded
with hydrophobic dihydroartemisinin (DHA) self-assemble into nanoparticles.
Importantly, conjugated DOX and DHA could be released quickly in a
weakly acidic environment by cleavage of the acid-sensitive acyl hydrazone
bond. Confocal microscopy and flow cytometry confirmed that these
PET-DOX/DHA nanoparticles efficiently delivered DOX into the nuclei
of MCF-7 cells. Significant tumor growth reduction was monitored in
a female C57BL/6 mouse model, showing that the PET-DOX/DHA nanoparticle-mediated
drug delivery system inhibited tumor growth and may improve therapy.
Thus, we have demonstrated that pectin may be useful in the design
of materials for biomedical applications.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.