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The self-assembly of nanostructures from conjugates of elastin-like peptides and collagen-like peptides (ELP-CLP) has been studied as means to produce thermoresponsive, collagen-binding drug delivery vehicles. Motivated by our previous work in which ELP-CLP conjugates successfully self-assembled into vesicles and platelet-like nanostructures, here, we extend our library of ELP-CLP bioconjugates to a series of tryptophan/phenylalanine-containing ELPs and GPO-based CLPs [W 2 F x - b -(GPO) y ] with various domain lengths to determine the impact of these modifications on the thermoresponsiveness and morphology. The lower transition temperature of the conjugates with longer ELP or CLP domains enables the formation of well-defined nanoparticles near physiological temperature. Moreover, the morphological transition from vesicles to platelet-like nanostructures occurred when the ratio of the lengths of ELP/CLP decreased. Given the previously demonstrated ability of many ELP-CLP bioconjugates to bind to both hydrophobic drugs and collagen-containing materials, our results suggest new opportunities for designing specific thermoresponsive nanostructures for targeted biological applications. 

Collagen-targeting strategies have proven to be an effective method for targeting drugs to pathological tissues for treatment of disease. The use of collagen-like peptides for controlling the assembly of drug delivery vehicles, as well as their integration into collagen-containing matrices, offers significant advantages for tuning the morphologies of assembled structures, their thermoresponsiveness, and the loading and release of both small-molecule and macro-molecular cargo. In this contribution, we summarize the design and development of collagen-peptide-based drug delivery systems introduced by the Kiick group and detail the expansion of our understanding and the application of these unique molecules through collaborations with experts in computational simulations (Jayaraman), osteoarthritis (Price), and gene delivery (Sullivan). Kiick was inducted as a Fellow of the National Academy of Inventors in 2019 and was to deliver an address describing the innovations of her research. Given the cancellation of the NAI Annual Meeting as a result of coronavirus travel restrictions, her work based on collagen-peptide-mediated assembly is instead summarized in this contribution. 

Elastin-like polypeptides (ELP) have been widely used in the biomaterials community due to their controllable, thermoresponsive properties and biocompatibility. Motivated by our previous work on the effect of tryptophan (W) substitutions on the LCST-like transitions of short ELPs, we studied a series of short ELPs containing tyrosine (Y) and/or phenylalanine (F) guest residues with only 5 or 6 pentapeptide repeat units. A combination of experiments and molecular dynamics (MD) simulations illustrated that the substitution of F with Y guest residues impacted the transition temperature ( T t ) of short ELPs when conjugated to collagen-like-peptides (CLP), with a reduction in the transition temperature observed only after substitution of at least two residues. Placement of the Y residues near the N-terminal end of the ELP, away from the tethering point to the CLP, resulted in a lower T t than that observed for peptides with the Y residues near the tethering point. Atomistic and coarse-grained MD simulations indicated an increase in intra- and inter-peptide hydrogen bonds in systems containing Y guest residues that are suggested to enhance the ability of the peptides to coacervate, with a concomitantly lower T t . Simulations also revealed that the placement of Y-containing pentads near the N-terminus ( i.e. , away from the CLP tethering point) versus C-terminus of the ELP led to more π–π stacking interactions at low temperatures, in agreement with our experimental observations of a lower T t . Overall, this study provides mechanistic insights into the driving forces for the LCST-like transitions of ELPs and offers additional means for tuning the T t of short ELPs for biomedical applications such as on-demand drug delivery and tissue engineering.