Many alkylated peptide amphiphiles have been reported to self-assemble into cylindrical nanofibers with diameters on the order of a few nanometers and micrometer scale lengths; these nanostructures can be highly bioactive and are of great interest in many biomedical applications. We have discovered the sequences for these molecules that can eliminate all curvature from the nanostructures they form in water and generate completely flat nanobelts with giant dimensions relative to previously reported systems. The nanobelts have fairly monodisperse widths on the order of 150 nm and lengths of up to 0.1 millimeters. The sequences have an alternating sequence with hydrophobic and hydrophilic side chains and variations in monomer concentration generate a "broom" morphology with twisted ribbons that reveals the mechanism through which giant nanobelts form. Interestingly, a variation in pH generates reversibly periodic 2nm grooves on the surfaces of the nanobelts. With proper functionalization, these nanostructures offer a novel architecture to present epitopes to cells for therapeutic applications.One-dimensional (1D) nanostructures have attracted extensive research interest over the past decade due to the beneficial influence of their dimensionality on electronic and optical materials properties 1-4 and very recently bioactivity combined with ability to crosslink into gel networks. 5-11 Interesting examples include the vapor deposition synthesis of carbon nanotubes 1 , semiconductor nanowires 2, 3 and nanobelts 4 , and on the soft matter side the selfassembly of cylindrical micelles 12, 13 , ribbons 14 and peptide nanofibers 5-7, 10, 11 . The key factor in formation of these 1D nanostructures is control of preferential growth in only one dimension. While both cylinders (one-dimensional growth) and membranes (two-dimensional growth) have been frequently reported through self-assembly of molecular building units 12, 15-17 , flat 1D nanostructures, namely nanobelts, are less common because of the difficulty of maintaining two significantly different growth rates along two different dimensions.Peptides or proteins with one or more β-sheet strands exhibit the extraordinary ability to assemble into long, fibrillar nanostructures via intermolecular hydrogen bonding. 5,6,[18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] Over the past few decades, extensive research efforts have been devoted to the structure and the formation mechanisms of amyloid fibers due to their links to neurodegenerative diseases 21-23 . In other work, there has been interest in 1D nanostructures formed by selfassembly of de novo designed peptides and peptidomimetics for their potential applications as biomaterials. 5,6,[24][25][26][27][28][29][30][31][37][38][39][40][41] Due to the intrinsic chirality of natural amino acids, the observed peptidic 1D nanostructures are often twisted or helical, and occasionally, they can *Corresponding author: E-mail: E-mail: s-stupp@northwestern.edu. Our previous work showed that a grea...

We report here a supramolecular strategy to directly assemble the small molecular hydrophobic anticancer drug camptothecin (CPT) into discrete, stable, well-defined nanostructures with a high and quantitative drug loading. Depending on the number of CPTs in the molecular design, the resulting nanostructures can be either nanofibers or nanotubes, and have a fixed CPT loading content ranging from 23% to 38%. We found that formation of nanostructures provides protection for both the CPT drug and the biodegradable linker from the external environment and thus offers a mechanism for controlled release of CPT. Under tumor-relevant conditions, these drug nanostructures can release the bioactive form of CPT and show in vitro efficacy against a number of cancer cell lines. This strategy can be extended to construct nanostructures of other types of anticancer drugs, and thus presents new opportunities for the development of self-delivering drugs for cancer therapeutics.

Peptide–drug conjugates (PDCs) represent an important class of therapeutic agents that combine one or more drug molecules with a short peptide through a biodegradable linker. This prodrug strategy uniquely and specifically exploits the biological activities and self-assembling potential of small molecule peptides to improve the treatment efficacy of medicinal compounds. We review here the recent progress in the design and synthesis of peptide–drug conjugates in the context of targeted drug delivery and cancer chemotherapy. We analyze carefully the key design features in choosing the peptide sequence and linker chemistry for the drug of interest, as well as the strategies to optimize the conjugate design. We highlight the recent progress in the design and synthesis of self-assembling peptide-drug amphiphiles to construct supramolecular nanomedicine and nanofiber hydrogels for both systemic and topical delivery of active pharmaceutical ingredients.

Covalent modification of therapeutic compounds is a clinically proven strategy to devise prodrugs with enhanced treatment efficacies. This prodrug strategy relies on modified drugs that possess advantageous pharmacokinetic properties and administration routes over their parent drug. Self-assembling prodrugs represent an emerging class of therapeutic agents capable of spontaneously associating into well-defined supramolecular nanostructures in aqueous solutions. The self-assembly of prodrugs expands the functional space of conventional prodrug design, providing a possible pathway to more effective therapies as the assembled nanostructure possesses distinct physicochemical properties that can be tailored to specific administration routes and disease treatment. In this review, we will discuss the various types of self-assembling prodrugs in development, providing an overview of the methods used to control their structure and function and, ultimately, our perspective on their current and future potential.

The switching of two adjacent amino acids can lead to differences in how proteins fold thus affecting their function. This effect has not been extensively explored in synthetic peptides in the context of supramolecular self-assembly. Toward this end, we report here the use of isomeric peptide amphiphiles as molecular building blocks to create one-dimensional (1D) nanostructures. We show that four peptide amphiphile isomers, with identical composition but a different sequence of their four amino acids, can form drastically different types of 1D nanostructures under the same conditions. We found that molecules with a peptide sequence of alternating hydrophobic and hydrophilic amino acids such as VEVE and EVEV self-assemble into flat nanostructures that can be either helical or twisted. On the other hand, nonalternating isomers such as VVEE and EEVV result in the formation of cylindrical nanofibers. Furthermore, we also found that when the glutamic acid is adjacent to the alkyl tail the supramolecular assemblies appear to be internally flexible compared to those with valine as the first amino acid. These results clearly demonstrate the significance of peptide side chain interactions in determining the architectures of supramolecular assemblies.