Collagen-Binding Peptide-Enabled Supramolecular Hydrogel Design for Improved Organ Adhesion and Sprayable Therapeutic Delivery

Caleb F Anderson; Rami W Chakroun; Maria E Grimmett; Christopher J Domalewski; Feihu Wang; Honggang Cui

doi:10.1021/acs.nanolett.2c00967

. Author manuscript; available in PMC: 2023 Jan 17.

Published in final edited form as: Nano Lett. 2022 May 6;22(10):4182–4191. doi: 10.1021/acs.nanolett.2c00967

Collagen-Binding Peptide-Enabled Supramolecular Hydrogel Design for Improved Organ Adhesion and Sprayable Therapeutic Delivery

Caleb F Anderson ^1,^⊥, Rami W Chakroun ^2,^3,^⊥, Maria E Grimmett ⁴, Christopher J Domalewski ⁵, Feihu Wang ⁶, Honggang Cui

PMCID: PMC9844543 NIHMSID: NIHMS1859479 PMID: 35522052

Abstract

Spraying serves as an attractive, minimally invasive means of administering hydrogels for localized delivery, particularly due to high-throughput deposition of therapeutic depots over an entire target site of uneven surfaces. However, it remains a great challenge to design systems capable of rapid gelation after shear-thinning during spraying and adhering to coated tissues in wet, physiological environments. We report here on the use of a collagen-binding peptide to enable a supramolecular design of a biocompatible, bioadhesive, and sprayable hydrogel for sustained release of therapeutics. After spraying, the designed peptide amphiphile-based supramolecular filaments exhibit fast, physical cross-linking under physiological conditions. Our ex vivo studies suggest that the hydrogelator strongly adheres to the wet surfaces of multiple organs, and the extent of binding to collagen influences release kinetics from the gel. We envision that the sprayable organ-adhesive hydrogel can serve to enhance the efficacy of incorporated therapeutics for many biomedical applications.

Keywords: molecular assembly, supramolecular filaments, hydrogels, drug delivery, sprayable materials, peptide amphiphiles

Graphical Abstract

graphic file with name nihms-1859479-f0006.jpg

Supramolecular hydrogels are attractive biomaterials for localized delivery, allowing for easy implantation of therapeutic agents at their target site while mitigating off-target effects, and thus, these systems have been extensively employed for a wide variety of biomedical applications, such as regenerative medicine,^1–11 tissue engineering,^12–23 drug delivery,^24–29 long-acting injectables,^31–34 and cancer immunotherapy.^35–37 Administration of hydrogels is commonly achieved through physical implantation or injection of the polymeric network with subsequent in situ cross-linking or gelation; in comparison, application via spraying is an attractive alternative to these methods due to its noninvasive nature and feasibility.^38–40 Particularly in the context of local delivery for surgical applications, such as post-tumor resection or wound cavity dressings, spraying is highly advantageous, as it provides high-throughput deposition of therapeutics directly to the entire target site of uneven surfaces for subsequent sustained release.^41–44

However, translation of sprayable gels to in vivo settings remains challenging due to a lack of adhesion of the materials in wet environments, which is essential for efficient retention on target tissues in bodily fluids and more controlled degradation profiles.^44–46 Through incorporation of bioadhesive peptides or proteins into the material design, hydrogels have been engineered to adhere to tissues, which has been demonstrated in some injectable systems with mussel-adhesive protein-inspired designs^47,48 and sprayable systems with fibrin gels.⁴⁹ For administration through spraying, it is key for the materials to exhibit shear-thinning properties to be capable of delivery in a sol-like state and then return to or cross-link in situ to a gel-like state;^50–52 therefore alongside tissue adhesion, the material design and mechanical properties are critical in developing sprayable hydrogels for biomedical applications.

In this context, we utilize the structural and biological role of peptides to create sprayable supramolecular hydrogels capable of organ-adhesion for local delivery of therapeutics. Self-assembling peptides, peptide amphiphiles, and other peptide-based conjugates are a class of molecular building units capable of spontaneously associating in aqueous solutions to form supramolecular hydrogels; these biomaterials are highly biocompatible, have been demonstrated to be shear-thinning with fast, reversible physical cross-linking, and can be easily functionalized with bioadhesive peptides, making them attractive candidates for developing adhesive sprayable hydrogels.^2,53–71 To this end, we designed a peptide amphiphile that incorporates a type I collagen-binding peptide sequence and self-assembles into filaments to subsequently form a supramolecular hydrogel in physiological conditions. The filaments exhibit rapid and spontaneous gelation after spraying and adhesion to many different organs in an ex vivo model.

RESULTS AND DISCUSSION

Molecular Design.

A peptide amphiphile (PA) molecule was designed to embody the characteristics necessary to develop an effective sprayable hydrogel delivery platform: self-assemble into a filamentous network that rapidly and spontaneously cross-links under physiological conditions, adhere to tissue surfaces, and exhibit high biocompatibility and biodegradability. The PA hydrogelator design (labeled CBPA) is composed of a hydrophilic peptide segment and hydrophobic alkyl chain (molecular design in Figure 1A, Figure S1).^2,72,73 The PA hydrophobic domain is composed of a dodecyl hydrocarbon chain (C₁₂ alkyl group) at its N-terminus to facilitate hydrophobic collapse for self-assembly in aqueous solutions. The hydrophilic domain is composed of a collagen-binding peptide sequence (LRELHLNNN) that exhibits a strong binding affinity to type I collagen (K_D = 1.7 × 10⁻⁷ M),^74–76 This peptide was chosen to facilitate binding of our system to type I collagen, which is the most abundant collagen type and functions as a key structural component of several tissues,⁷⁷ and therefore by incorporating this sequence, it is likely that the resulting supramolecular structures formed by CBPA will exhibit broad adhesive properties. The CBPA monomers can spontaneously associate in aqueous solutions to form supramolecular filaments, and then in the presence of physiologically relevant counterions, salt screening facilitates rapid physical entanglement of filaments to form a hydrogel (Figure 1B).

Figure 1. — Molecular design, self-assembly characterization, and gelation properties of collagen-binding PA (CBPA)filaments before and after spraying. (A) Chemical structure of CBPA with the type I collagen-binding peptide sequence, LRELHLNNN, highlighted in blue. (B) Schematic representation of the self-assembly of CBPA monomers into supramolecular filaments in aqueous environments and subsequent hydrogel formation by filament entanglement in the presence of counterions. (C) Representative transmission electron microscopy (TEM) and scanning electron microscopy (SEM) images of CBPA supramolecular filaments (1 mM in water) and hydrogel network (4 mM in 1× PBS), where images on the left are before spraying and on the right are after spraying with an atomizer. Filament diameters are represented as the mean ± SD (ns p > 0.05, unpaired two-tailed t test with Welch’s correction, n = 35). Images represent CBPA gels at critical gelation concentration (1 mM) after vial inversion for the before and after spraying conditions.

Molecular Assembly and Filament Characterization.

After synthesizing CBPA, we studied its self-assembly behavior and the impacts of spraying on its supramolecular structure, as shear forces generated during spraying may disrupt the noncovalent interactions that facilitate assembly.^78,79 After dissolution in water, CBPA is observed to self-assemble into flexible filaments over several microns in length with a diameter measuring around ~11 nm (Figure 1C). Upon addition of counterions from PBS to achieve afinal 1× PBS concentration in solution, the filaments are capable of entangling to form a self-supporting hydrogel within seconds (left gel image Figure 1C) and exhibit a critical gelation concentration (CGC) at ~1 mM. The filament network within the hydrogel (4 mM) contains intertwined and twisted filaments, supporting the influence of physical cross-linking in gelation (Figure 1C). After spraying with a mucosal atomizer, filaments were observed to maintain their shape and remain several micrometers long; however, more instances of filament ends were observed, which suggests some fragmentation does occur. In some instances, multiple filaments are observed to show a high degree of lateral alignment and bundling, which is likely due to shear as liquid droplets are emitted from the atomizer nozzle (Figures 1C, S2, and S3).⁸⁰ Despite the filament alignment and minimal fragmentation, the sprayed CBPA filaments maintain their ability to form a self-supporting hydrogel at the same concentration (right gel image Figure 1C).

Spraying Impact on Gelation Properties.

We next aimed to further explore the gelation properties of CBPA filaments and the influence of spraying on its rheology and cytotoxicity, as spraying of the material should ideally negligibly impact these properties. Filament solutions (1 mM) exhibit fluid-like rheological properties until addition of 10× PBS at 2 min, which results in an increase in the storage modulus (G′) and stabilization of the loss modulus (G″) with the crossover point (G′ > G″) occurring roughly 15 slater, suggestive of more solid-like rheological properties and the formation of a gel (Figure 2A). Spraying shows minimal impact on the stiffness of the resulting CBPA gels, as sprayed gels appear only slightly mechanically weaker, which is likely reflective of the supramolecular stability of the CBPA filaments (critical micelle concentration (CMC) of CBPA was calculated to be ~2.2 μM).^81–84 Spraying also showed minimal impact on molecular packing of CBPA within filaments by circular dichroism (Figure 2B).

Figure 2. — Influence of spraying on gelation properties, degradation, and biocompatibility of CBPA filaments. (A) Rheological assessment by oscillatory time-sweep measurement showing changes in storage (G′, circles) and loss modulus (G″, open circles) over the course of 10 min for normal (blue) and sprayed (red) gels at room temperature. (B) Circular dichroism spectra of normal and sprayed CBPA filaments in water. Data represent mean spectra for each solution (n = 3). (C) Gel degradation profile of normal and sprayed CBPA gels (1 mM) into PBS at 37 °C taken at an equal time interval over the course of 30 days. Data are presented as the mean ± SD (n = 3); dashed lines represent results of linear regression analysis (****p < 0.0001 between slopes, ANCOVA). (D) Representative live/dead staining fluorescence microscopy images of 3T3 fibroblasts cultured atop normal (G) and sprayed (SG) 2 mM CBPA gels after 7 days, where green fluorescence indicates living cell and red indicates dead cell. Scale bars represent 50 μm. (E) Cell viability of 3T3 fibroblasts cultured atop 2 mM normal (G) and sprayed (SG) CBPA gels over the course of 7 days as determined from live/dead staining. Data are represented as the mean ± SD (ns p > 0.05 across days and gel types, two-way ANOVA with Sidak post hoc test, n = 5). (F) Cell metabolism of 3T3 fibroblasts cultured atop 2 mM normal (G) and sprayed (SG) CBPA gels over the course of 7 days as determined by PrestoBlue assay. Data are represented as the mean ± SD (*p < 0.05, ns p > 0.05, ****p < 0.0001 across days, two-way ANOVA with Sidak post hoc test, n = 5).

Next, we aimed to evaluate the impacts of spraying on the degradation rate of CBPA gels in vitro. We observe linear degradationof CBPA gels over the course of a month into PBS at 37 °C, where approximately 2.5% (by mass) of initial CBPA is lost and around 7.5% for the sprayed gel, which is a likely predictor of long-term release characteristics (Figure 2C). The degradation rate was measured to be around 3-fold higher for the sprayed gel (0.23%/day vs 0.08%/day) in comparison. In the context of the previously explored mechanism of supramolecular gel release,⁶³ the increased degradation rate of the sprayed gel is likely reflective of filament network alignment/bundling which can in turn impact gel swelling from larger pore sizes, which is corroborated by TEM and SEM results. In the context of biomedical applications, this faster rate may be advantageous for mitigating potential adverse side effects that arise from long-term implantation.⁸⁵

Given the structural stability of CBPA filaments to form self-supporting hydrogels after spraying, we next assessed the biocompatibility of the gel by evaluating its cytotoxicity. Over the course of 7 days, NIH/3T3 fibroblasts were cultured on the surface of both normal and sprayed CBPA gels, where cell viability remained above 95%, as evidenced by live/dead staining for both normal and sprayed gels (Figure 2D, Figure S5), suggesting CBPA gels are not cytotoxic (Figure 2E). Micrographs show cell spreading, suggesting adherence to the gel surface, and high cell confluency by day 7 (Figure 2D). The metabolic activity of the fibroblasts was probed by PrestoBlue assay, which showed great increase in relative fluorescence over time, evidencing the ability of cells to proliferate and maintain metabolism on CBPA gels (Figure 2F). The lower relative fluorescence of the sprayed gel measured on day 7 may be reflective of its weaker stiffness, which can slow cell growth.⁸⁶ Collectively, these results demonstrate the biocompatibility of the CBPA gel.

Adhesion of CBPA Gels to Organ Surfaces.

With validation of the maintained rheological properties and biocompatibility of the CBPA gel after spraying, we next aimed to assess the ability of the gel to be sprayed on and bind to the surface of multiple organs. To assess this qualitatively, we obtained organs from a lamb to assess ex vivo binding of CBPA gels to the lungs, liver, spleen, and kidney (Figure S6, methylene blue dissolved in gels for better visualization). By use of an atomizer, organs were sprayed with CBPA filaments (4 mM, coating of lung shown in Supporting Information Video 1) and then immediately submerged into 1× PBS for a few seconds to mimic the wetness of bodily fluids/cavities and then removed, where detachment of CBPA gel was visualized. For the lung, the CBPA gel exhibits strong binding to the lung exterior surface with some gel lost around the edges after submersion (Figure 3Ai,Aii, Supporting Information Video 2), which was also observed for the interior surface (Figure 3Aiii,Aiv). To confirm that the adhesion is due to the collagen-binding ability of the CBPA design, we synthesized a cell-binding PA control, which contains the RGDR peptide sequence at its C-terminus, known for cellular integrin and neuropilin-1 association,^87,88 and exhibits a similar CGC as CBPA (likely due to design containing the same C₁₂ alkyl chain, Figure S7). By the submersion test, the control PA exhibits negligible adhesion to external lung and kidney tissue while CBPA exhibits greater adherence (Figure 3D, Figure S8, Supporting Information Video 3, Supporting Information Video 4), highlighting the significance of the collagen-binding property in achieving adhesion of the gel to collagen-containing tissues. For the other harvested organs, CBPA exhibits low binding potential to the liver and kidney (Figure 3B, Supporting Information Video 5, Supporting Information Video 6). On the spleen, however, the CBPA gel shows strong adhesion to the spleen exterior, where no noticeable loss of gel is observed after submersion (Figure 3C, Supporting Information Video 7). The ability of the CBPA gel to adhere to different organs is thus likely reflective of the type I collagen content of the coated tissue; nevertheless, these ex vivo results highlight the broad applicability of the CBPA gel to adhere to several major organs in a wet environment.

Figure 3. — *Ex vivo* organ adhesion of sprayed CBPA gel by qualitative assessment with submersion test from a variety of organs harvested from a lamb. (A) Lung exterior surface (i) before and (ii) after submersion in PBS, alongside interior surface (iii) before and (iv) after submersion in PBS. (B) Liver exterior surface (i) before and (ii) after submersion in PBS, alongside interior surface (iii) before and (iv) after submersion in PBS. (C) Spleen exterior surface (i) before and (ii) after submerging in PBS. (D) Kidney exterior surface (i) before and (ii) after submerging in PBS, alongside its interior surface (iii) before being sprayed, (iv) after spraying, and (v) after submersion in PBS. All organs were coated with CBPA gels prepared at 4 mM and loaded with methylene blue dye for easier visualization.

Spraying of CBPA Gels by Nebulization.

From our ex vivo examination of the adhesion of CBPA gels to different organs, the ability of the gel to adhere to both the internal and external surfaces of the lungs was very striking. Given the collagen content of the lungs,⁸⁹ we aimed to further investigate if the CBPA gel could be sprayed as finer respirable aerosol droplets, which could extend the applicability of the gel, such as for use as a noninvasive sealant.⁴¹ However, given the additional air–liquid interface interactions presented during respirable aerosol formation, the capability of the filaments to form a hydrogel could be severely hindered.⁸⁴ Therefore, we assessed the gelation behavior of CBPA filaments after spraying with a jet nebulizer (Figure S9), a common medical device that generates liquid aerosol droplets (ranging in diameter from 1 to 10 μm, as opposed to the 30–100 μm droplets produced from atomizers).⁹⁰

After jet nebulization, collected CBPA filaments exhibit reduced contour length to varying degrees (Figure 4A, Figure S10), as expected.⁸⁴ Interestingly, despite the greater extent of observed filament length reduction, the nebulized CBPA filaments can still form a self-supporting hydrogel with the same CGC (insert in Figure 4A), which is likely imparted by its high supramolecular stability (Figures S4 and S11).⁸⁴ However, the in vitro degradation of nebulized CBPA gels shows a distinct two-phase profile: an initial burst phase that occurs during the first 2 weeks followed by a slow linear phase (Figure 4B). We hypothesize that the burst phase is in part due to oversaturation of the bulk fluid with monomers of CBPA from interface enrichment during aerosol formation,⁸⁴ which likely exhibit slower reassembly into filamentous structures after gel formation. In conjunction with the shorter filaments, which will facilitate faster swelling, the monomers quickly diffuse out of the gel network into the surrounding media. After depletion of the excess CBPA monomers, the gel degrades at a slower, linear rate; this rate is very similar to the rate observed for the sprayed system (around 0.26 vs 0.23% (by mass)/day, p > 0.05 by linear regression ANCOVA), which likely reflects a similar degree of porosity induced by shear from the two methods of spraying.

With the imparted faster degradation pattern, we assessed if nebulization would negatively impact the biocompatibility of the CBPA gel. Over the course of a week, fibroblasts maintain high cell viability above 95% and spread atop and adhere to nebulized gels (Figure 4C,D and Figure S12) while also proliferating and maintaining metabolic activity (Figure 4E), demonstrating that the biocompatibility of the CBPA gel is negligibly impacted by nebulization. We hypothesize that the reduced metabolic activity observed here in comparison to the sprayed gel (Figure 2F) is likely from reduced cell substrate stiffness imparted by the observed greater reduction in filament contour length.

Diffusion of Cancer Drug Conjugate from Collagen-Binding Gels.

We next aimed to further showcase the broad applicability of the collagen-binding hydrogel system to disease contexts while also studying the impacts of adhesion to tissues on the release of loaded therapeutics. In the context of cancer therapy, spraying our system in a postsurgical tumor resection cavity could afford complete covering and adhesion to the cavity followed by sustainable release of chemotherapeutics to kill remaining cancer cells. To achieve this, we replaced the alkyl chain in our design of CBPA with the anticancer drug, paclitaxel (PTX), to yield a collagen-binding drug amphiphile, called CBDA, with similar design features for self-assembly and binding activity (Figure 5A and Figure S13). Paclitaxel is conjugated directly to the collagen-binding peptide through a biodegradable, reducible disulfide linker, which is cleaved by intracellular glutathione to release free PTX.^91,92 These peptide–drug conjugates have been previously demonstrated to be self-formulating and maintain similar levels of cytotoxicity as free PTX.^42,63,91,93 CBDA self-assembles into filaments after dissolution in water, which can subsequently entangle after addition of PBS to form a solid hydrogel at a CGC of ~1 mM (similar CGC to CBPA likely due to identical peptide segment, Figure 5A,B).

Figure 5. — Degradation of collagen-binding gels and diffusion of loaded drug conjugates. (A) Chemical structure of the collagen-binding drug amphiphile, CBDA, composed of hydrophobic anticancer drug, paclitaxel (red), conjugated through a reducible disulfide linker (green) to the type I collagen-binding peptide (blue), LRELHLNNN. (B) Representative transmission electron microscopy (TEM) image of CBDA filaments (1 mM in water). Filament diameter is represented as the mean ± SD (n = 35). Inset image represents sprayed CBDA gel at critical gelation concentration (1 mM) after vial inversion. (C) Schematic representation of spraying CBDA gels into resection cavities covering different surface areas. (D) Release profiles of CBDA monomers from gels sprayed onto the surfaces of harvested lamb spleen of different sizes into surrounding 1× PBS solution at 37 °C over the course of 10 days (small = 0.875 cm², medium = 1.8 cm², and large = 3.8 cm²). Data are represented as the mean ± SD (n = 3); dashed lines represent results of linear regression analysis (****p < 0.0001 among slopes, ANCOVA). (E) Schematic representation of experimental design to simulate diffusion of CBPA from sprayed gels into coated tissue using collagen gels. (F) Measured relative fluorescence intensity/area from sprayed 5FAM-conjugated CBPA (2 mM in water) diffusion into high density rat-tail type I collagen gel (2 mg/mL) at different depths over the course of 72 h. Data are represented as the mean ± SD (n = 5).

In the context of spraying into a tumor resection cavity, CBDA monomers can either diffuse into the fluid occupying the cavity or permeate into the tissue coated by the gel. Therefore, we first aimed to assess the release rate of CBDA from the surface of organs of different sizes into surrounding media, as the extent of gel in contact with collagen will likely influence its degradation and release (Figure 5C). We sprayed equivalent doses of CBDA filaments onto the surface of harvested lamb spleen cut into varying surface areas (Figure S14): small (0.875 cm²), medium (1.8 cm²), and large (3.8 cm²). The organs were submerged in PBS, and the rate of CBDA discharge into surrounding fluid was measured over 10 days. We observe that for the same dose of CBDA filaments, the larger the surface area it coats, the slower is the release of drug conjugate from the gel into its surroundingfluid (Figure 5D). The release rate of CBDA measures around 10.1 μg/day·cm² for the smallest area, 3.9 μg/day·cm² for the medium area, and 0.7 μg/day·cm² for the largest area tested, which suggests that spraying the same dose over larger areas will expose the gel to more potential binding sites of collagen, reducing the ratio of available collagen fibrils to supramolecular filaments, thereby enhancing the organ-adhering properties of the gel and minimizing degradation into the surrounding cavity. On the other hand, localizing the filaments to a smaller organ surface results in saturation of available binding sites, which in turn leads to stacking or layering of filaments, stimulating the breakdown of filaments on the superficial layers of the gel, which are in limited contact with collagen fibrils. However, for each organ size, the breakdown of the filament coating did not exceed 20% of the total conjugate. This highlights the favorable retention of the filaments to the organ surface, allowing for a long-term release of drug conjugate throughout the target site.

We next aimed to evaluate the diffusion of the conjugates into a coated tissue, where we simulated this in vitro by spraying the gels atop high-density rat-tail type I collagen gels (Figure 5E). To visualize penetration into the collagen gel, we synthesized a fluorescent analogue of CBPA with 5-carboxyfluoroscein and a similar CGC (Figure S15). Quantifying diffusion over the course of 72 h by fluorescence, we observe a slow increase in intensity that quickly increases to its saturation point from 24 to 48 h, where the observed intensity is highest at the top (position 1) of the collagen gel nearest the CBPA gel and lowest at the bottom (position 30) of the collagen gel (Figure 5F). We hypothesize that the delayed spike in measured intensity is likely due to impeded diffusion of CBPA monomers by binding interactions with collagen, where, as the availability of binding sites on the collagen gel decreases, more monomers can diffuse through the gel as likely driven by the concentration gradient. Altogether, these results highlight the critical role of the collagen-binding interaction in influencing the rate of degradation and diffusion of the gels while also showcasing the means of extending applicability of the platform through direct conjugation of therapeutics and dyes.

Herein, we demonstrate a major advantage of self-assembling peptide conjugates for use as sprayable, bioadhesive supramolecular hydrogelators. Through rational molecular design, we developed a peptide conjugate platform that possesses the key properties for successful translation as a sprayable hydrogel for localized delivery. First, through use of peptide amphiphiles, we form filamentous nanostructures with suitable structural stability and rheological properties to maintain capability of rapid, reversible cross-linking after spraying (through both atomization and nebulization) to yield solid hydrogels. Second, through incorporation of type I collagen-binding peptide sequence, the gel strongly adheres to the wet surfaces of various organs, as evidenced with our ex vivo model. For the current design, however, challenges remain in applicability to every region of the body; for tissues that are deficient in type I collagen, the gel will likely demonstrate suboptimal adhesion, limiting efficacy. Additionally, on the basis of application location, regular body movement may disrupt the hydrogel network, also limiting efficacy. Despite these challenges, the PA-based hydrogel can be readily adapted to fit its intended location and application, such as through incorporation of other peptide sequences that bind to other structural tissue components for better adhesion and increasing the supramolecular cohesiveness of the filamentous structures for improved mechanical properties.

Supplementary Material

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Supp Video 1

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Supp Video 3

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ACKNOWLEDGMENTS

The work reported here is supported by National Science Foundation (Grant DMR 1255281). C.F.A. acknowledges support of National Institutes of Health Predoctoral Training Program (Grant 5T32 CA 153952). R.W.C. acknowledges support from the National Science Foundation Graduate Research Fellowship Program (Grant DGE 1746891). We thank the Integrated Imaging Center (IIC) at Johns Hopkins University for the use of the TEM facility and the Johns Hopkins University Department of Chemistry Mass Spectroscopy for use of the MALDI-TOF instrument.

Footnotes

The authors declare no competing financial interest.

ASSOCIATED CONTENT

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.nanolett.2c00967.

Details of molecular synthesis and characterization, additional TEM and SEM images of the supramolecular filaments before and after spraying, CD measurements, CMC measurements, additional live/dead staining fluorescence micrographs of fibroblasts cultured on CBPA gels, and fluid and PA release curves from a jet nebulizer (PDF)

Video 1 showing spraying of CBPA filament solution (4 mM) onto the external surface of lamb lung using an atomizer (MP4)

Video 2 of submersion test on external lung surface after coating with CBPA filaments (4 mM) via spraying (MP4)

Video 3 of submersion test on external lung surface after coating with CBPA filaments (4 mM) via spraying (MP4)

Video 4 of submersion test on external lung surface after coating with cell-binding control PA filaments (4 mM) via spraying (MP4)

Video 5 of submersion test on external liver surface after coating with CBPA filaments (4 mM) via spraying (MP4)

Video 6 of submersion test on external kidney surface after coating with CBPA filaments (4 mM) via spraying (MP4)

Video 7 of submersion test on external spleen surface after coating with CBPA filaments (4 mM) via spraying (MP4)

Complete contact information is available at: https://pubs.acs.org/10.1021/acs.nanolett.2c00967

Contributor Information

Caleb F. Anderson, Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States.

Rami W. Chakroun, Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States; Department of Chemical Engineering and Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

Maria E. Grimmett, Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States

Christopher J. Domalewski, Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States

Feihu Wang, Department of Chemical and Biomolecular Engineering and Institute for NanoBioTechnology, Johns Hopkins University, Baltimore, Maryland 21218, United States.

REFERENCES

(1).Alvarez Z; Kolberg-Edelbrock AN; Sasselli IR; Ortega JA; Qiu R; Syrgiannis Z; Mirau PA; Chen F; Chin SM; Weigand S; Kiskinis E; Stupp SI Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury. Science 2021, 374 (6569), 848–856. [DOI] [PMC free article] [PubMed] [Google Scholar]
(2).Cui H; Webber MJ; Stupp SI Self-assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials. Peptide Science 2010, 94 (1), 1–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
(3).Lin BF; Megley KA; Viswanathan N; Krogstad DV; Drews LB; Kade MJ; Qian Y; Tirrell MV pH-responsive branched peptide amphiphile hydrogel designed for applications in regenerative medicine with potential as injectable tissue scaffolds. J. Mater. Chem. 2012, 22 (37), 19447–19454. [Google Scholar]
(4).Acar H; Srivastava S; Chung EJ; Schnorenberg MR; Barrett JC; LaBelle JL; Tirrell M Self-assembling peptide-based building blocks in medical applications. Adv. Drug Delivery Rev. 2017, 110–111, 65–79. [DOI] [PMC free article] [PubMed] [Google Scholar]
(5).Ananthanarayanan B; Little L; Schaffer DV; Healy KE; Tirrell M Neural stem cell adhesion and proliferation on phospholipid bilayers functionalized with RGD peptides. Biomaterials 2010, 31 (33), 8706–8715. [DOI] [PMC free article] [PubMed] [Google Scholar]
(6).Webber MJ; Tongers J; Newcomb CJ; Marquardt K-T; Bauersachs J; Losordo DW; Stupp SI Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (33), 13438. [DOI] [PMC free article] [PubMed] [Google Scholar]
(7).Parmar PA; Skaalure SC; Chow LW; St-Pierre J-P; Stoichevska V; Peng YY; Werkmeister JA; Ramshaw JAM; Stevens MM Temporally degradable collagen–mimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells. Biomaterials 2016, 99, 56–71. [DOI] [PMC free article] [PubMed] [Google Scholar]
(8).Lopez-Silva TL; Cristobal CD; Edwin Lai CS; Leyva-Aranda V; Lee HK; Hartgerink JD Self-assembling multidomain peptide hydrogels accelerate peripheral nerve regeneration after crush injury. Biomaterials 2021, 265, 120401. [DOI] [PMC free article] [PubMed] [Google Scholar]
(9).Gaharwar AK; Singh I; Khademhosseini A Engineered biomaterials for in situ tissue regeneration. Nature Reviews Materials 2020, 5 (9), 686–705. [Google Scholar]
(10).Chow LW; Bitton R; Webber MJ; Carvajal D; Shull KR; Sharma AK; Stupp SI A bioactive self-assembled membrane to promote angiogenesis. Biomaterials 2011, 32 (6), 1574–1582. [DOI] [PMC free article] [PubMed] [Google Scholar]
(11).Edelbrock AN; Àllvarez Z; Simkin D; Fyrner T; Chin SM; Sato K; Kiskinis E; Stupp SI Supramolecular Nanostructure Activates TrkB Receptor Signaling of Neuronal Cells by Mimicking Brain-Derived Neurotrophic Factor. Nano Lett. 2018, 18 (10), 623–6247. [DOI] [PMC free article] [PubMed] [Google Scholar]
(12).Sleep E; Cosgrove BD; McClendon MT; Preslar AT; Chen CH; Sangji MH; Pérez CMR; Haynes RD; Meade TJ; Blau HM; Stupp SI Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (38), E7919. [DOI] [PMC free article] [PubMed] [Google Scholar]
(13).Pakalns T; Haverstick K. l.; Fields GB; McCarthy JB; Mooradian D. l.; Tirrell M. Cellular recognition of synthetic peptide amphiphiles in self-assembled monolayer films. Biomaterials 1999, 20 (2–24), 226–2279. [DOI] [PubMed] [Google Scholar]
(14).Galler KM; Aulisa L; Regan KR; D’Souza RN; Hartgerink JD Self-assembling multidomain peptide hydrogels: designed susceptibility to enzymatic cleavage allows enhanced cell migration and spreading. J. Am. Chem. Soc. 2010, 132 (9), 321–3223. [DOI] [PMC free article] [PubMed] [Google Scholar]
(15).Webber MJ; Tongers J; Renault M-A; Roncalli JG; Losordo DW; Stupp SI Development of bioactive peptide amphiphile sfor therapeutic cell delivery. Acta Biomaterialia 2010, 6 (1), 3–11. [DOI] [PMC free article] [PubMed] [Google Scholar]
(16).Silva GA; Czeisler C; Niece KL; Beniash E; Harrington DA; Kessler JA; Stupp SI Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 2004, 303 (5662), 135–1355. [DOI] [PubMed] [Google Scholar]
(17).Parmar PA; Chow LW; St-Pierre J-P; Horejs C-M; Peng YY; Werkmeister JA; Ramshaw JAM; Stevens MM Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. Biomaterials 2015, 54, 21–225. [DOI] [PMC free article] [PubMed] [Google Scholar]
(18).Godbe JM; Freeman R; Burbulla LF; Lewis J; Krainc D; Stupp SI Gelator Length Precisely Tunes Supramolecular Hydrogel Stiffness and Neuronal Phenotype in 3D Culture. ACS Biomaterials Science & Engineering 2020, 6 (2), 119–1207. [DOI] [PMC free article] [PubMed] [Google Scholar]
(19).Freeman R; Stephanopoulos N; Álvarez Z; Lewis JA; Sur S; Serrano CM; Boekhoven J; Lee SS; Stupp SI Instructing cells with programmable peptide DNA hybrids. Nat. Commun. 2017, 8 (1), 15982. [DOI] [PMC free article] [PubMed] [Google Scholar]
(20).Freeman R; Han M; Alvarez Z; Lewis JA; Wester JR; Stephanopoulos N; McClendon MT; Lynsky C; Godbe JM; Sangji H; Luijten E; Stupp SI Reversible self-assembly of superstructured networks. Science 2018, 362 (6416), 808–813. [DOI] [PMC free article] [PubMed] [Google Scholar]
(21).Du Y; Lo E; Ali S; Khademhosseini A Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (28), 9522. [DOI] [PMC free article] [PubMed] [Google Scholar]
(22).Camacho P; Busari H; Seims KB; Schwarzenberg P; Dailey HL; Chow LW 3D printing with peptide–polymer conjugates for single-step fabrication of spatially functionalized scaffolds. Biomaterials Science 2019, 7 (10), 4237–4247. [DOI] [PubMed] [Google Scholar]
(23).Camacho P; Behre A; Fainor M; Seims KB; Chow LW Spatial organization of biochemical cues in 3D-printed scaffolds to guide osteochondral tissue engineering. Biomaterials Science 2021, 9, 6813–6829. [DOI] [PubMed] [Google Scholar]
(24).Li J; Mooney DJ Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 2016, 1 (12), 16071. [DOI] [PMC free article] [PubMed] [Google Scholar]
(25).Zhao F; Ma ML; Xu B Molecular hydrogels of therapeutic agents. Chem. Soc. Rev. 2009, 38 (4), 883–891. [DOI] [PubMed] [Google Scholar]
(26).Wang F; Su H; Lin R; Chakroun RW; Monroe MK; Wang Z; Porter M; Cui H Supramolecular Tubustecan Hydrogel as Chemotherapeutic Carrier to Improve Tumor Penetration and Local Treatment Efficacy. ACS Nano 2020, 14 (8), 10083–10094. [DOI] [PubMed] [Google Scholar]
(27).Bernhard S; Tibbitt MW Supramolecular engineering of hydrogels for drug delivery. Adv. Drug Delivery Rev. 2021, 171, 240–256. [DOI] [PubMed] [Google Scholar]
(28).Webber MJ; Langer R Drug delivery by supramolecular design. Chem. Soc. Rev. 2017, 46 (21), 6600–6620. [DOI] [PubMed] [Google Scholar]
(29).He H; Liu S; Wu D; Xu B Enzymatically Formed Peptide Assemblies Sequestrate Proteins and Relocate Inhibitors to Selectively Kill Cancer Cells. Angew. Chem., Int. Ed. 2020, 59 (38), 16445–16450. [DOI] [PMC free article] [PubMed] [Google Scholar]
(30).Kumar VA; Shi S; Wang BK; Li IC; Jalan AA; Sarkar B; Wickremasinghe NC; Hartgerink JD Drug-Triggered and Cross-Linked Self-Assembling Nanofibrous Hydrogels. J. Am. Chem. Soc. 2015, 137 (14), 4823–4830. [DOI] [PMC free article] [PubMed] [Google Scholar]
(31).Haines-Butterick L; Rajagopal K; Branco M; Salick D; Rughani R; Pilarz M; Lamm MS; Pochan DJ; Schneider JP Controlling hydrogelation kinetics by peptide design for three-dimensional encapsulation and injectable delivery of cells. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (19), 7791. [DOI] [PMC free article] [PubMed] [Google Scholar]
(32).Altunbas A; Lee SJ; Rajasekaran SA; Schneider JP; Pochan DJ Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials 2011, 32 (25), 5906–5914. [DOI] [PMC free article] [PubMed] [Google Scholar]
(33).Yu S; Xian S; Ye Z; Pramudya I; Webber MJ Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation. J. Am. Chem. Soc. 2021, 143 (32), 12578–12589. [DOI] [PubMed] [Google Scholar]
(34).Clarke DE; Pashuck ET; Bertazzo S; Weaver JVM; Stevens MM Self-Healing, Self-Assembled β-Sheet Peptide–Poly(γ-glutamic acid) Hybrid Hydrogels. J. Am. Chem. Soc. 2017, 139 (21), 7250–7255. [DOI] [PMC free article] [PubMed] [Google Scholar]
(35).Wang F; Su H; Xu D; Dai W; Zhang W; Wang Z; Anderson CF; Zheng M; Oh R; Wan F; Cui H Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel. Nature Biomedical Engineering 2020, 4 (11), 1090–1101. [DOI] [PMC free article] [PubMed] [Google Scholar]
(36).Wang F; Xu D; Su H; Zhang W; Sun X; Monroe MK; Chakroun RW; Wang Z; Dai W; Oh R; Wang H; Fan Q; Wan F; Cui H Supramolecular prodrug hydrogelator as an immune booster for checkpoint blocker-based immunotherapy. Sci. Adv. 2020, 6 (18), eaaz8985. [DOI] [PMC free article] [PubMed] [Google Scholar]
(37).Leach DG; Dharmaraj N; Lopez-Silva TL; Venzor JR; Pogostin BH; Sikora AG; Hartgerink JD; Young S Biomaterial-Facilitated Immunotherapy for Established Oral Cancers. ACS Biomaterials Science & Engineering 2021, 7 (2), 415–421. [DOI] [PMC free article] [PubMed] [Google Scholar]
(38).Sahoo JK; VandenBerg MA; Webber MJ Injectable network biomaterials via molecular or colloidal self-assembly. Adv. Drug Delivery Rev. 2018, 127, 185–207. [DOI] [PubMed] [Google Scholar]
(39).Si Y; Wen Y; Kelly SH; Chong AS; Collier JH Intranasal delivery of adjuvant-free peptide nanofibers elicits resident CD8+ T cell responses. J. Controlled Release 2018, 282, 120–130. [DOI] [PMC free article] [PubMed] [Google Scholar]
(40).Mahmud A; Harada T; Rajagopal K; Christian DA; Nair P; Murphy R; Discher DE Spray stability of self-assembled filaments for delivery. J. Controlled Release 2017, 263, 162–171. [DOI] [PMC free article] [PubMed] [Google Scholar]
(41).Annabi N; Zhang Y-N; Assmann A; Sani ES; Cheng G; Lassaletta AD; Vegh A; Dehghani B; Ruiz-Esparza GU; Wang X; Gangadharan S; Weiss AS; Khademhosseini A Engineering a highly elastic human protein-based sealant for surgical applications. Sci. Transl. Med. 2017, 9 (410), eaai7466. [DOI] [PMC free article] [PubMed] [Google Scholar]
(42).Chakroun RW; Wang F; Lin R; Wang Y; Su H; Pompa D; Cui H Fine-Tuning the Linear Release Rate of Paclitaxel-Bearing Supramolecular Filament Hydrogels through Molecular Engineering. ACS Nano 2019, 13 (7), 7780–7790. [DOI] [PubMed] [Google Scholar]
(43).Schiapparelli P; Zhang P; Lara-Velazquez M; Guerrero-Cazares H; Lin R; Su H; Chakroun RW; Tusa M; Quiñones-Hinojosa A; Cui H Self-assembling and self-formulating prodrug hydrogelator extends survival in a glioblastoma resection and recurrence model. J. Controlled Release 2020, 319, 31–321. [DOI] [PubMed] [Google Scholar]
(44).Jeong Y; Jo YK; Kim BJ; Yang B; Joo KI; Cha HJ Sprayable Adhesive Nanotherapeutics: Mussel-Protein-Based Nanoparticles for Highly Efficient Locoregional Cancer Therapy. ACS Nano 2018, 12 (9), 890–8919. [DOI] [PubMed] [Google Scholar]
(45).Zhang Y-N; Avery RK; Vallmajo-Martin Q; Assmann A; Vegh A; Memic A; Olsen BD; Annabi N; Khademhosseini A A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications. Adv. Funct. Mater. 2015, 25 (30), 4814–4826. [DOI] [PMC free article] [PubMed] [Google Scholar]
(46).Tavafoghi M; Sheikhi A; Tutar R; Jahangiry J; Baidya A; Haghniaz R; Khademhosseini A Engineering Tough, Injectable, Naturally Derived, Bioadhesive Composite Hydrogels. Adv. Healthcare Mater. 2020, 9 (10), 1901722. [DOI] [PMC free article] [PubMed] [Google Scholar]
(47).Jeon EY; Choi B-H; Jung D; Hwang BH; Cha HJ Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration. Biomaterials 2017, 134, 154–165. [DOI] [PubMed] [Google Scholar]
(48).Li L; Yan B; Yang J; Chen L; Zeng H Novel Mussel-Inspired Injectable Self-Healing Hydrogel with Anti-Biofouling Property. Adv. Mater. 2015, 27 (7), 1294–1299. [DOI] [PubMed] [Google Scholar]
(49).Chen Q; Wang C; Zhang X; Chen G; Hu Q; Li H; Wang J; Wen D; Zhang Y; Lu Y; Yang G; Jiang C; Wang J; Dotti G; Gu Z In situ sprayed bioresponsive immunotherapeutic gel for postsurgical cancer treatment. Nat. Nanotechnol. 2019, 14 (1), 89–97. [DOI] [PubMed] [Google Scholar]
(50).Xu D; Hawk JL; Loveless DM; Jeon SL; Craig SL Mechanism of Shear Thickening in Reversibly Cross-Linked Supramolecular Polymer Networks. Macromolecules 2010, 43 (7), 3556–3565. [DOI] [PMC free article] [PubMed] [Google Scholar]
(51).Xu D; Liu C-Y; Craig SL Divergent Shear Thinning and Shear Thickening Behavior of Supramolecular Polymer Networks in Semidilute Entangled Polymer Solutions. Macromolecules 2011, 44 (7), 2343–2353. [DOI] [PMC free article] [PubMed] [Google Scholar]
(52).Marco-Dufort B; Iten R; Tibbitt MW Linking Molecular Behavior to Macroscopic Properties in Ideal Dynamic Covalent Networks. J. Am. Chem. Soc. 2020, 142 (36), 15371–15385. [DOI] [PubMed] [Google Scholar]
(53).Berndt P; Fields GB; Tirrell M Synthetic lipidation of peptides and amino acids: monolayer structure and properties. J. Am. Chem. Soc. 1995, 117 (37), 9515–9522. [Google Scholar]
(54).Hartgerink JD; Beniash E; Stupp SI Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 2001, 294 (5547), 1684. [DOI] [PubMed] [Google Scholar]
(55).Gao Y; Kuang Y; Guo Z-F; Guo Z; Krauss IJ; Xu B Enzyme-instructed molecular self-assembly confers nanofibers and a supramolecular hydrogel of Taxol derivative. J. Am. Chem. Soc. 2009, 131 (38), 13576–13577. [DOI] [PubMed] [Google Scholar]
(56).Pashuck ET; Cui H; Stupp SI Tuning Supramolecular Rigidity of Peptide Fibers through Molecular Structure. J. Am. Chem. Soc. 2010, 132 (17), 6041–6046. [DOI] [PMC free article] [PubMed] [Google Scholar]
(57).Soukasene S; Toft DJ; Moyer TJ; Lu H; Lee H-K; Standley SM; Cryns VL; Stupp SI Antitumor Activity of Peptide Amphiphile Nanofiber-Encapsulated Camptothecin. ACS Nano 2011, 5 (11), 9113–9121. [DOI] [PMC free article] [PubMed] [Google Scholar]
(58).Yan C; Altunbas A; Yucel T; Nagarkar RP; Schneider JP; Pochan DJ Injectable solid hydrogel: mechanism of shear-thinning and immediate recovery of injectable β-hairpin peptide hydrogels. Soft Matter 2010, 6 (20), 5143–5156. [DOI] [PMC free article] [PubMed] [Google Scholar]
(59).Zhang P; Cheetham AG; Lin Y.-a.; Cui H Self-Assembled Tat Nanofibers as Effective Drug Carrier and Transporter. ACS Nano 2013, 7 (7), 5965–5977. [DOI] [PMC free article] [PubMed] [Google Scholar]
(60).Black M; Trent A; Kostenko Y; Lee JS; Olive C; Tirrell M Self-Assembled Peptide Amphiphile Micelles Containing a Cytotoxic T-Cell Epitope Promote a Protective Immune Response In Vivo. Adv. Mater. 2012, 24 (28), 3845–3849. [DOI] [PubMed] [Google Scholar]
(61).Pappas CG; Shafi R; Sasselli IR; Siccardi H; Wang T; Narang V; Abzalimov R; Wijerathne N; Ulijn RV Dynamic peptide libraries for the discovery of supramolecular nanomaterials. Nat. Nanotechnol. 2016, 11 (11), 960–967. [DOI] [PubMed] [Google Scholar]
(62).Jin H; Wan C; Zou Z; Zhao G; Zhang L; Geng Y; Chen T; Huang A; Jiang F; Feng J-P; Lovell JF; Chen J; Wu G; Yang K Tumor Ablation and Therapeutic Immunity Induction by an Injectable Peptide Hydrogel. ACS Nano 2018, 12 (4), 3295–3310. [DOI] [PubMed] [Google Scholar]
(63).Chakroun RW; Sneider A; Anderson CF; Wang F; Wu P-H; Wirtz D; Cui H Supramolecular Design of Unsymmetric Reverse Bolaamphiphiles for Cell-Sensitive Hydrogel Degradation and Drug Release. Angew. Chem., Int. Ed. 2020, 59 (11), 4434–4442. [DOI] [PubMed] [Google Scholar]
(64).O’Leary LER; Fallas JA; Bakota EL; Kang MK; Hartgerink JD Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. Nat. Chem. 2011, 3 (10), 821–828. [DOI] [PubMed] [Google Scholar]
(65).Wang S-T; Lin Y; Spencer RK; Thomas MR; Nguyen AI; Amdursky N; Pashuck ET; Skaalure SC; Song CY; Parmar PA; Morgan RM; Ercius P; Aloni S; Zuckermann RN; Stevens MM Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils. ACS Nano 2017, 11 (9), 8579–8589. [DOI] [PMC free article] [PubMed] [Google Scholar]
(66).Yang Z; Gu H; Fu D; Gao P; Lam JK; Xu B Enzymatic Formation of Supramolecular Hydrogels. Adv. Mater. 2004, 16 (16), 1440–1444. [Google Scholar]
(67).Yu Y-C; Berndt P; Tirrell M; Fields GB Self-Assembling Amphiphiles for Construction of Protein Molecular Architecture. J. Am. Chem. Soc. 1996, 118 (50), 12515–12520. [Google Scholar]
(68).Yu Y-C; Tirrell M; Fields GB Minimal Lipidation Stabilizes Protein-Like Molecular Architecture. J. Am. Chem. Soc. 1998, 120 (39), 9979–9987. [Google Scholar]
(69).Pashuck ET; Duchet BJR; Hansel CS; Maynard SA; Chow LW; Stevens MM Controlled Sub-Nanometer Epitope Spacing in a Three-Dimensional Self-Assembled Peptide Hydrogel. ACS Nano 2016, 10 (12), 11096–11104. [DOI] [PubMed] [Google Scholar]
(70).Lin Y; Penna M; Thomas MR; Wojciechowski JP; Leonardo V; Wang Y; Pashuck ET; Yarovsky I; Stevens MM Residue-Specific Solvation-Directed Thermodynamic and Kinetic Control over Peptide Self-Assembly with 1D/2D Structure Selection. ACS Nano 2019, 13 (2), 1900–1909. [DOI] [PMC free article] [PubMed] [Google Scholar]
(71).Hartgerink JD; Beniash E; Stupp SI Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (8), 5133. [DOI] [PMC free article] [PubMed] [Google Scholar]
(72).Sai H; Lau GC; Dannenhoffer AJ; Chin SM; Dordevic L; Stupp SI Imaging Supramolecular Morphogenesis with Confocal Laser ScanningMicroscopy at Elevated Temperatures. Nano Lett. 2020, 20 (6), 4234–4241. [DOI] [PubMed] [Google Scholar]
(73).Sangji MH; Sai H; Chin SM; Lee SR; Sasselli IR; Palmer LC; Stupp SI Supramolecular Interactions and Morphology of Self-Assembling Peptide Amphiphile Nanostructures. Nano Lett. 2021, 21 (14), 6146–6155. [DOI] [PubMed] [Google Scholar]
(74).Federico S; Pierce BF; Piluso S; Wischke C; Lendlein A; Neffe AT Design of Decorin-Based Peptides That Bind to Collagen I and their Potential as Adhesion Moieties in Biomaterials. Angew. Chem., Int. Ed. 2015, 54 (37), 10980–10984. [DOI] [PubMed] [Google Scholar]
(75).Schönherr E; Hausser H; Beavan L; Kresse H Decorin-Type I Collagen Interaction: Presence of Separate Core Protein-Binding Domains. J. Biol. Chem. 1995, 270 (15), 8877–8883. [DOI] [PubMed] [Google Scholar]
(76).Scott PG; McEwan PA; Dodd CM; Bergmann EM; Bishop PN; Bella J Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan. Proc. Natl. Acad. Sci. U.S.A. 2004, 101 (44), 15633. [DOI] [PMC free article] [PubMed] [Google Scholar]
(77).Shoulders MD; Raines RT Collagen Structure and Stability. Annu. Rev. Biochem. 2009, 78 (1), 929–958. [DOI] [PMC free article] [PubMed] [Google Scholar]
(78).Zhang X; Wang J; Jin H; Wang S; Song W Bioinspired Supramolecular Lubricating Hydrogel Induced by Shear Force. J. Am. Chem. Soc. 2018, 140 (9), 3186–3189. [DOI] [PubMed] [Google Scholar]
(79).Webber MJ; Appel EA; Meijer EW; Langer R Supramolecular biomaterials. Nat. Mater. 2016, 15 (1), 13–26. [DOI] [PubMed] [Google Scholar]
(80).Wester JR; Lewis JA; Freeman R; Sai H; Palmer LC; Henrich SE; Stupp SI Supramolecular Exchange among Assemblies of Opposite Charge Leads to Hierarchical Structures. J. Am. Chem. Soc. 2020, 142 (28), 12216–12225. [DOI] [PubMed] [Google Scholar]
(81).Tantakitti F; Boekhoven J; Wang X; Kazantsev RV; Yu T; Li J; Zhuang E; Zandi R; Ortony JH; Newcomb CJ; Palmer LC; Shekhawat GS; de la Cruz MO; Schatz GC; Stupp SI Energy landscapes and functions of supramolecular systems. Nat. Mater. 2016, 15 (4), 469–476. [DOI] [PMC free article] [PubMed] [Google Scholar]
(82).da Silva RMP; van der Zwaag D; Albertazzi L; Lee SS; Meijer EW; Stupp SI Super-resolution microscopy reveals structural diversity in molecular exchange among peptide amphiphile nanofibres. Nat. Commun. 2016, 7 (1), 11561. [DOI] [PMC free article] [PubMed] [Google Scholar]
(83).Chen CH; Palmer LC; Stupp SI Self-Repair of Structure and Bioactivity in a Supramolecular Nanostructure. Nano Lett. 2018, 18 (11), 6832–6841. [DOI] [PMC free article] [PubMed] [Google Scholar]
(84).Anderson CF; Chakroun RW; Su H; Mitrut RE; Cui H Interface-Enrichment-Induced Instability and Drug-Loading-Enhanced Stability in Inhalable Delivery of Supramolecular Filaments. ACS Nano 2019, 13 (11), 12957–12968. [DOI] [PMC free article] [PubMed] [Google Scholar]
(85).Park H; Park K Biocompatibility Issues of Implantable Drug Delivery Systems. Pharm. Res. 1996, 13 (12), 1770–1776. [DOI] [PubMed] [Google Scholar]
(86).Discher DE; Janmey P; Wang Y.-l. Tissue Cells Feel and Respond to the Stiffness of Their Substrate. Science 2005, 310 (5751), 1139. [DOI] [PubMed] [Google Scholar]
(87).Bellis SL Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials 2011, 32 (18), 4205–4210. [DOI] [PMC free article] [PubMed] [Google Scholar]
(88).Sugahara KN; Teesalu T; Karmali PP; Kotamraju VR; Agemy L; Greenwald DR; Ruoslahti E Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science 2010, 328 (5981), 1031. [DOI] [PMC free article] [PubMed] [Google Scholar]
(89).Bradley KH; McConnell SD; Crystal RG Lung collagen composition and synthesis: Characterization and changes with age. J. Biol. Chem. 1974, 249 (9), 2674–2683. [PubMed] [Google Scholar]
(90).Anderson CF; Grimmett ME; Domalewski CJ; Cui H Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases. WIREs Nanomed. Nanobiotechnol. 2020, 12 (1), e1586. [DOI] [PMC free article] [PubMed] [Google Scholar]
(91).Lin R; Cheetham AG; Zhang P; Lin Y.-a.; Cui H Supramolecular filaments containing a fixed 41% paclitaxel loading. Chem. Commun. 2013, 49 (43), 4968–4970. [DOI] [PMC free article] [PubMed] [Google Scholar]
(92).Dubikovskaya EA; Thorne SH; Pillow TH; Contag CH; Wender PA Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (34), 12128. [DOI] [PMC free article] [PubMed] [Google Scholar]
(93).Cheetham AG; Zhang P; Lin Y.-a.; Lock LL; Cui H Supramolecular Nanostructures Formed by Anticancer Drug Assembly. J. Am. Chem. Soc. 2013, 135 (8), 2907–2910. [DOI] [PMC free article] [PubMed] [Google Scholar]

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[R1] (1).Alvarez Z; Kolberg-Edelbrock AN; Sasselli IR; Ortega JA; Qiu R; Syrgiannis Z; Mirau PA; Chen F; Chin SM; Weigand S; Kiskinis E; Stupp SI Bioactive scaffolds with enhanced supramolecular motion promote recovery from spinal cord injury. Science 2021, 374 (6569), 848–856. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R2] (2).Cui H; Webber MJ; Stupp SI Self-assembly of peptide amphiphiles: From molecules to nanostructures to biomaterials. Peptide Science 2010, 94 (1), 1–18. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R3] (3).Lin BF; Megley KA; Viswanathan N; Krogstad DV; Drews LB; Kade MJ; Qian Y; Tirrell MV pH-responsive branched peptide amphiphile hydrogel designed for applications in regenerative medicine with potential as injectable tissue scaffolds. J. Mater. Chem. 2012, 22 (37), 19447–19454. [Google Scholar]

[R4] (4).Acar H; Srivastava S; Chung EJ; Schnorenberg MR; Barrett JC; LaBelle JL; Tirrell M Self-assembling peptide-based building blocks in medical applications. Adv. Drug Delivery Rev. 2017, 110–111, 65–79. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R5] (5).Ananthanarayanan B; Little L; Schaffer DV; Healy KE; Tirrell M Neural stem cell adhesion and proliferation on phospholipid bilayers functionalized with RGD peptides. Biomaterials 2010, 31 (33), 8706–8715. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] (6).Webber MJ; Tongers J; Newcomb CJ; Marquardt K-T; Bauersachs J; Losordo DW; Stupp SI Supramolecular nanostructures that mimic VEGF as a strategy for ischemic tissue repair. Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (33), 13438. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] (7).Parmar PA; Skaalure SC; Chow LW; St-Pierre J-P; Stoichevska V; Peng YY; Werkmeister JA; Ramshaw JAM; Stevens MM Temporally degradable collagen–mimetic hydrogels tuned to chondrogenesis of human mesenchymal stem cells. Biomaterials 2016, 99, 56–71. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] (8).Lopez-Silva TL; Cristobal CD; Edwin Lai CS; Leyva-Aranda V; Lee HK; Hartgerink JD Self-assembling multidomain peptide hydrogels accelerate peripheral nerve regeneration after crush injury. Biomaterials 2021, 265, 120401. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] (9).Gaharwar AK; Singh I; Khademhosseini A Engineered biomaterials for in situ tissue regeneration. Nature Reviews Materials 2020, 5 (9), 686–705. [Google Scholar]

[R10] (10).Chow LW; Bitton R; Webber MJ; Carvajal D; Shull KR; Sharma AK; Stupp SI A bioactive self-assembled membrane to promote angiogenesis. Biomaterials 2011, 32 (6), 1574–1582. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] (11).Edelbrock AN; Àllvarez Z; Simkin D; Fyrner T; Chin SM; Sato K; Kiskinis E; Stupp SI Supramolecular Nanostructure Activates TrkB Receptor Signaling of Neuronal Cells by Mimicking Brain-Derived Neurotrophic Factor. Nano Lett. 2018, 18 (10), 623–6247. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] (12).Sleep E; Cosgrove BD; McClendon MT; Preslar AT; Chen CH; Sangji MH; Pérez CMR; Haynes RD; Meade TJ; Blau HM; Stupp SI Injectable biomimetic liquid crystalline scaffolds enhance muscle stem cell transplantation. Proc. Natl. Acad. Sci. U. S. A. 2017, 114 (38), E7919. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R13] (13).Pakalns T; Haverstick K. l.; Fields GB; McCarthy JB; Mooradian D. l.; Tirrell M. Cellular recognition of synthetic peptide amphiphiles in self-assembled monolayer films. Biomaterials 1999, 20 (2–24), 226–2279. [DOI] [PubMed] [Google Scholar]

[R14] (14).Galler KM; Aulisa L; Regan KR; D’Souza RN; Hartgerink JD Self-assembling multidomain peptide hydrogels: designed susceptibility to enzymatic cleavage allows enhanced cell migration and spreading. J. Am. Chem. Soc. 2010, 132 (9), 321–3223. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R15] (15).Webber MJ; Tongers J; Renault M-A; Roncalli JG; Losordo DW; Stupp SI Development of bioactive peptide amphiphile sfor therapeutic cell delivery. Acta Biomaterialia 2010, 6 (1), 3–11. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R16] (16).Silva GA; Czeisler C; Niece KL; Beniash E; Harrington DA; Kessler JA; Stupp SI Selective differentiation of neural progenitor cells by high-epitope density nanofibers. Science 2004, 303 (5662), 135–1355. [DOI] [PubMed] [Google Scholar]

[R17] (17).Parmar PA; Chow LW; St-Pierre J-P; Horejs C-M; Peng YY; Werkmeister JA; Ramshaw JAM; Stevens MM Collagen-mimetic peptide-modifiable hydrogels for articular cartilage regeneration. Biomaterials 2015, 54, 21–225. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R18] (18).Godbe JM; Freeman R; Burbulla LF; Lewis J; Krainc D; Stupp SI Gelator Length Precisely Tunes Supramolecular Hydrogel Stiffness and Neuronal Phenotype in 3D Culture. ACS Biomaterials Science & Engineering 2020, 6 (2), 119–1207. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] (19).Freeman R; Stephanopoulos N; Álvarez Z; Lewis JA; Sur S; Serrano CM; Boekhoven J; Lee SS; Stupp SI Instructing cells with programmable peptide DNA hybrids. Nat. Commun. 2017, 8 (1), 15982. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] (20).Freeman R; Han M; Alvarez Z; Lewis JA; Wester JR; Stephanopoulos N; McClendon MT; Lynsky C; Godbe JM; Sangji H; Luijten E; Stupp SI Reversible self-assembly of superstructured networks. Science 2018, 362 (6416), 808–813. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] (21).Du Y; Lo E; Ali S; Khademhosseini A Directed assembly of cell-laden microgels for fabrication of 3D tissue constructs. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (28), 9522. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R22] (22).Camacho P; Busari H; Seims KB; Schwarzenberg P; Dailey HL; Chow LW 3D printing with peptide–polymer conjugates for single-step fabrication of spatially functionalized scaffolds. Biomaterials Science 2019, 7 (10), 4237–4247. [DOI] [PubMed] [Google Scholar]

[R23] (23).Camacho P; Behre A; Fainor M; Seims KB; Chow LW Spatial organization of biochemical cues in 3D-printed scaffolds to guide osteochondral tissue engineering. Biomaterials Science 2021, 9, 6813–6829. [DOI] [PubMed] [Google Scholar]

[R24] (24).Li J; Mooney DJ Designing hydrogels for controlled drug delivery. Nat. Rev. Mater. 2016, 1 (12), 16071. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] (25).Zhao F; Ma ML; Xu B Molecular hydrogels of therapeutic agents. Chem. Soc. Rev. 2009, 38 (4), 883–891. [DOI] [PubMed] [Google Scholar]

[R26] (26).Wang F; Su H; Lin R; Chakroun RW; Monroe MK; Wang Z; Porter M; Cui H Supramolecular Tubustecan Hydrogel as Chemotherapeutic Carrier to Improve Tumor Penetration and Local Treatment Efficacy. ACS Nano 2020, 14 (8), 10083–10094. [DOI] [PubMed] [Google Scholar]

[R27] (27).Bernhard S; Tibbitt MW Supramolecular engineering of hydrogels for drug delivery. Adv. Drug Delivery Rev. 2021, 171, 240–256. [DOI] [PubMed] [Google Scholar]

[R28] (28).Webber MJ; Langer R Drug delivery by supramolecular design. Chem. Soc. Rev. 2017, 46 (21), 6600–6620. [DOI] [PubMed] [Google Scholar]

[R29] (29).He H; Liu S; Wu D; Xu B Enzymatically Formed Peptide Assemblies Sequestrate Proteins and Relocate Inhibitors to Selectively Kill Cancer Cells. Angew. Chem., Int. Ed. 2020, 59 (38), 16445–16450. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R30] (30).Kumar VA; Shi S; Wang BK; Li IC; Jalan AA; Sarkar B; Wickremasinghe NC; Hartgerink JD Drug-Triggered and Cross-Linked Self-Assembling Nanofibrous Hydrogels. J. Am. Chem. Soc. 2015, 137 (14), 4823–4830. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R31] (31).Haines-Butterick L; Rajagopal K; Branco M; Salick D; Rughani R; Pilarz M; Lamm MS; Pochan DJ; Schneider JP Controlling hydrogelation kinetics by peptide design for three-dimensional encapsulation and injectable delivery of cells. Proc. Natl. Acad. Sci. U. S. A. 2007, 104 (19), 7791. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R32] (32).Altunbas A; Lee SJ; Rajasekaran SA; Schneider JP; Pochan DJ Encapsulation of curcumin in self-assembling peptide hydrogels as injectable drug delivery vehicles. Biomaterials 2011, 32 (25), 5906–5914. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R33] (33).Yu S; Xian S; Ye Z; Pramudya I; Webber MJ Glucose-Fueled Peptide Assembly: Glucagon Delivery via Enzymatic Actuation. J. Am. Chem. Soc. 2021, 143 (32), 12578–12589. [DOI] [PubMed] [Google Scholar]

[R34] (34).Clarke DE; Pashuck ET; Bertazzo S; Weaver JVM; Stevens MM Self-Healing, Self-Assembled β-Sheet Peptide–Poly(γ-glutamic acid) Hybrid Hydrogels. J. Am. Chem. Soc. 2017, 139 (21), 7250–7255. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R35] (35).Wang F; Su H; Xu D; Dai W; Zhang W; Wang Z; Anderson CF; Zheng M; Oh R; Wan F; Cui H Tumour sensitization via the extended intratumoural release of a STING agonist and camptothecin from a self-assembled hydrogel. Nature Biomedical Engineering 2020, 4 (11), 1090–1101. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R36] (36).Wang F; Xu D; Su H; Zhang W; Sun X; Monroe MK; Chakroun RW; Wang Z; Dai W; Oh R; Wang H; Fan Q; Wan F; Cui H Supramolecular prodrug hydrogelator as an immune booster for checkpoint blocker-based immunotherapy. Sci. Adv. 2020, 6 (18), eaaz8985. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R37] (37).Leach DG; Dharmaraj N; Lopez-Silva TL; Venzor JR; Pogostin BH; Sikora AG; Hartgerink JD; Young S Biomaterial-Facilitated Immunotherapy for Established Oral Cancers. ACS Biomaterials Science & Engineering 2021, 7 (2), 415–421. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R38] (38).Sahoo JK; VandenBerg MA; Webber MJ Injectable network biomaterials via molecular or colloidal self-assembly. Adv. Drug Delivery Rev. 2018, 127, 185–207. [DOI] [PubMed] [Google Scholar]

[R39] (39).Si Y; Wen Y; Kelly SH; Chong AS; Collier JH Intranasal delivery of adjuvant-free peptide nanofibers elicits resident CD8+ T cell responses. J. Controlled Release 2018, 282, 120–130. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R40] (40).Mahmud A; Harada T; Rajagopal K; Christian DA; Nair P; Murphy R; Discher DE Spray stability of self-assembled filaments for delivery. J. Controlled Release 2017, 263, 162–171. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R41] (41).Annabi N; Zhang Y-N; Assmann A; Sani ES; Cheng G; Lassaletta AD; Vegh A; Dehghani B; Ruiz-Esparza GU; Wang X; Gangadharan S; Weiss AS; Khademhosseini A Engineering a highly elastic human protein-based sealant for surgical applications. Sci. Transl. Med. 2017, 9 (410), eaai7466. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R42] (42).Chakroun RW; Wang F; Lin R; Wang Y; Su H; Pompa D; Cui H Fine-Tuning the Linear Release Rate of Paclitaxel-Bearing Supramolecular Filament Hydrogels through Molecular Engineering. ACS Nano 2019, 13 (7), 7780–7790. [DOI] [PubMed] [Google Scholar]

[R43] (43).Schiapparelli P; Zhang P; Lara-Velazquez M; Guerrero-Cazares H; Lin R; Su H; Chakroun RW; Tusa M; Quiñones-Hinojosa A; Cui H Self-assembling and self-formulating prodrug hydrogelator extends survival in a glioblastoma resection and recurrence model. J. Controlled Release 2020, 319, 31–321. [DOI] [PubMed] [Google Scholar]

[R44] (44).Jeong Y; Jo YK; Kim BJ; Yang B; Joo KI; Cha HJ Sprayable Adhesive Nanotherapeutics: Mussel-Protein-Based Nanoparticles for Highly Efficient Locoregional Cancer Therapy. ACS Nano 2018, 12 (9), 890–8919. [DOI] [PubMed] [Google Scholar]

[R45] (45).Zhang Y-N; Avery RK; Vallmajo-Martin Q; Assmann A; Vegh A; Memic A; Olsen BD; Annabi N; Khademhosseini A A Highly Elastic and Rapidly Crosslinkable Elastin-Like Polypeptide-Based Hydrogel for Biomedical Applications. Adv. Funct. Mater. 2015, 25 (30), 4814–4826. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R46] (46).Tavafoghi M; Sheikhi A; Tutar R; Jahangiry J; Baidya A; Haghniaz R; Khademhosseini A Engineering Tough, Injectable, Naturally Derived, Bioadhesive Composite Hydrogels. Adv. Healthcare Mater. 2020, 9 (10), 1901722. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R47] (47).Jeon EY; Choi B-H; Jung D; Hwang BH; Cha HJ Natural healing-inspired collagen-targeting surgical protein glue for accelerated scarless skin regeneration. Biomaterials 2017, 134, 154–165. [DOI] [PubMed] [Google Scholar]

[R48] (48).Li L; Yan B; Yang J; Chen L; Zeng H Novel Mussel-Inspired Injectable Self-Healing Hydrogel with Anti-Biofouling Property. Adv. Mater. 2015, 27 (7), 1294–1299. [DOI] [PubMed] [Google Scholar]

[R49] (49).Chen Q; Wang C; Zhang X; Chen G; Hu Q; Li H; Wang J; Wen D; Zhang Y; Lu Y; Yang G; Jiang C; Wang J; Dotti G; Gu Z In situ sprayed bioresponsive immunotherapeutic gel for postsurgical cancer treatment. Nat. Nanotechnol. 2019, 14 (1), 89–97. [DOI] [PubMed] [Google Scholar]

[R50] (50).Xu D; Hawk JL; Loveless DM; Jeon SL; Craig SL Mechanism of Shear Thickening in Reversibly Cross-Linked Supramolecular Polymer Networks. Macromolecules 2010, 43 (7), 3556–3565. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R51] (51).Xu D; Liu C-Y; Craig SL Divergent Shear Thinning and Shear Thickening Behavior of Supramolecular Polymer Networks in Semidilute Entangled Polymer Solutions. Macromolecules 2011, 44 (7), 2343–2353. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R52] (52).Marco-Dufort B; Iten R; Tibbitt MW Linking Molecular Behavior to Macroscopic Properties in Ideal Dynamic Covalent Networks. J. Am. Chem. Soc. 2020, 142 (36), 15371–15385. [DOI] [PubMed] [Google Scholar]

[R53] (53).Berndt P; Fields GB; Tirrell M Synthetic lipidation of peptides and amino acids: monolayer structure and properties. J. Am. Chem. Soc. 1995, 117 (37), 9515–9522. [Google Scholar]

[R54] (54).Hartgerink JD; Beniash E; Stupp SI Self-assembly and mineralization of peptide-amphiphile nanofibers. Science 2001, 294 (5547), 1684. [DOI] [PubMed] [Google Scholar]

[R55] (55).Gao Y; Kuang Y; Guo Z-F; Guo Z; Krauss IJ; Xu B Enzyme-instructed molecular self-assembly confers nanofibers and a supramolecular hydrogel of Taxol derivative. J. Am. Chem. Soc. 2009, 131 (38), 13576–13577. [DOI] [PubMed] [Google Scholar]

[R56] (56).Pashuck ET; Cui H; Stupp SI Tuning Supramolecular Rigidity of Peptide Fibers through Molecular Structure. J. Am. Chem. Soc. 2010, 132 (17), 6041–6046. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R57] (57).Soukasene S; Toft DJ; Moyer TJ; Lu H; Lee H-K; Standley SM; Cryns VL; Stupp SI Antitumor Activity of Peptide Amphiphile Nanofiber-Encapsulated Camptothecin. ACS Nano 2011, 5 (11), 9113–9121. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R58] (58).Yan C; Altunbas A; Yucel T; Nagarkar RP; Schneider JP; Pochan DJ Injectable solid hydrogel: mechanism of shear-thinning and immediate recovery of injectable β-hairpin peptide hydrogels. Soft Matter 2010, 6 (20), 5143–5156. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R59] (59).Zhang P; Cheetham AG; Lin Y.-a.; Cui H Self-Assembled Tat Nanofibers as Effective Drug Carrier and Transporter. ACS Nano 2013, 7 (7), 5965–5977. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R60] (60).Black M; Trent A; Kostenko Y; Lee JS; Olive C; Tirrell M Self-Assembled Peptide Amphiphile Micelles Containing a Cytotoxic T-Cell Epitope Promote a Protective Immune Response In Vivo. Adv. Mater. 2012, 24 (28), 3845–3849. [DOI] [PubMed] [Google Scholar]

[R61] (61).Pappas CG; Shafi R; Sasselli IR; Siccardi H; Wang T; Narang V; Abzalimov R; Wijerathne N; Ulijn RV Dynamic peptide libraries for the discovery of supramolecular nanomaterials. Nat. Nanotechnol. 2016, 11 (11), 960–967. [DOI] [PubMed] [Google Scholar]

[R62] (62).Jin H; Wan C; Zou Z; Zhao G; Zhang L; Geng Y; Chen T; Huang A; Jiang F; Feng J-P; Lovell JF; Chen J; Wu G; Yang K Tumor Ablation and Therapeutic Immunity Induction by an Injectable Peptide Hydrogel. ACS Nano 2018, 12 (4), 3295–3310. [DOI] [PubMed] [Google Scholar]

[R63] (63).Chakroun RW; Sneider A; Anderson CF; Wang F; Wu P-H; Wirtz D; Cui H Supramolecular Design of Unsymmetric Reverse Bolaamphiphiles for Cell-Sensitive Hydrogel Degradation and Drug Release. Angew. Chem., Int. Ed. 2020, 59 (11), 4434–4442. [DOI] [PubMed] [Google Scholar]

[R64] (64).O’Leary LER; Fallas JA; Bakota EL; Kang MK; Hartgerink JD Multi-hierarchical self-assembly of a collagen mimetic peptide from triple helix to nanofibre and hydrogel. Nat. Chem. 2011, 3 (10), 821–828. [DOI] [PubMed] [Google Scholar]

[R65] (65).Wang S-T; Lin Y; Spencer RK; Thomas MR; Nguyen AI; Amdursky N; Pashuck ET; Skaalure SC; Song CY; Parmar PA; Morgan RM; Ercius P; Aloni S; Zuckermann RN; Stevens MM Sequence-Dependent Self-Assembly and Structural Diversity of Islet Amyloid Polypeptide-Derived β-Sheet Fibrils. ACS Nano 2017, 11 (9), 8579–8589. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R66] (66).Yang Z; Gu H; Fu D; Gao P; Lam JK; Xu B Enzymatic Formation of Supramolecular Hydrogels. Adv. Mater. 2004, 16 (16), 1440–1444. [Google Scholar]

[R67] (67).Yu Y-C; Berndt P; Tirrell M; Fields GB Self-Assembling Amphiphiles for Construction of Protein Molecular Architecture. J. Am. Chem. Soc. 1996, 118 (50), 12515–12520. [Google Scholar]

[R68] (68).Yu Y-C; Tirrell M; Fields GB Minimal Lipidation Stabilizes Protein-Like Molecular Architecture. J. Am. Chem. Soc. 1998, 120 (39), 9979–9987. [Google Scholar]

[R69] (69).Pashuck ET; Duchet BJR; Hansel CS; Maynard SA; Chow LW; Stevens MM Controlled Sub-Nanometer Epitope Spacing in a Three-Dimensional Self-Assembled Peptide Hydrogel. ACS Nano 2016, 10 (12), 11096–11104. [DOI] [PubMed] [Google Scholar]

[R70] (70).Lin Y; Penna M; Thomas MR; Wojciechowski JP; Leonardo V; Wang Y; Pashuck ET; Yarovsky I; Stevens MM Residue-Specific Solvation-Directed Thermodynamic and Kinetic Control over Peptide Self-Assembly with 1D/2D Structure Selection. ACS Nano 2019, 13 (2), 1900–1909. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R71] (71).Hartgerink JD; Beniash E; Stupp SI Peptide-amphiphile nanofibers: A versatile scaffold for the preparation of self-assembling materials. Proc. Natl. Acad. Sci. U. S. A. 2002, 99 (8), 5133. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R72] (72).Sai H; Lau GC; Dannenhoffer AJ; Chin SM; Dordevic L; Stupp SI Imaging Supramolecular Morphogenesis with Confocal Laser ScanningMicroscopy at Elevated Temperatures. Nano Lett. 2020, 20 (6), 4234–4241. [DOI] [PubMed] [Google Scholar]

[R73] (73).Sangji MH; Sai H; Chin SM; Lee SR; Sasselli IR; Palmer LC; Stupp SI Supramolecular Interactions and Morphology of Self-Assembling Peptide Amphiphile Nanostructures. Nano Lett. 2021, 21 (14), 6146–6155. [DOI] [PubMed] [Google Scholar]

[R74] (74).Federico S; Pierce BF; Piluso S; Wischke C; Lendlein A; Neffe AT Design of Decorin-Based Peptides That Bind to Collagen I and their Potential as Adhesion Moieties in Biomaterials. Angew. Chem., Int. Ed. 2015, 54 (37), 10980–10984. [DOI] [PubMed] [Google Scholar]

[R75] (75).Schönherr E; Hausser H; Beavan L; Kresse H Decorin-Type I Collagen Interaction: Presence of Separate Core Protein-Binding Domains. J. Biol. Chem. 1995, 270 (15), 8877–8883. [DOI] [PubMed] [Google Scholar]

[R76] (76).Scott PG; McEwan PA; Dodd CM; Bergmann EM; Bishop PN; Bella J Crystal structure of the dimeric protein core of decorin, the archetypal small leucine-rich repeat proteoglycan. Proc. Natl. Acad. Sci. U.S.A. 2004, 101 (44), 15633. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R77] (77).Shoulders MD; Raines RT Collagen Structure and Stability. Annu. Rev. Biochem. 2009, 78 (1), 929–958. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R78] (78).Zhang X; Wang J; Jin H; Wang S; Song W Bioinspired Supramolecular Lubricating Hydrogel Induced by Shear Force. J. Am. Chem. Soc. 2018, 140 (9), 3186–3189. [DOI] [PubMed] [Google Scholar]

[R79] (79).Webber MJ; Appel EA; Meijer EW; Langer R Supramolecular biomaterials. Nat. Mater. 2016, 15 (1), 13–26. [DOI] [PubMed] [Google Scholar]

[R80] (80).Wester JR; Lewis JA; Freeman R; Sai H; Palmer LC; Henrich SE; Stupp SI Supramolecular Exchange among Assemblies of Opposite Charge Leads to Hierarchical Structures. J. Am. Chem. Soc. 2020, 142 (28), 12216–12225. [DOI] [PubMed] [Google Scholar]

[R81] (81).Tantakitti F; Boekhoven J; Wang X; Kazantsev RV; Yu T; Li J; Zhuang E; Zandi R; Ortony JH; Newcomb CJ; Palmer LC; Shekhawat GS; de la Cruz MO; Schatz GC; Stupp SI Energy landscapes and functions of supramolecular systems. Nat. Mater. 2016, 15 (4), 469–476. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R82] (82).da Silva RMP; van der Zwaag D; Albertazzi L; Lee SS; Meijer EW; Stupp SI Super-resolution microscopy reveals structural diversity in molecular exchange among peptide amphiphile nanofibres. Nat. Commun. 2016, 7 (1), 11561. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R83] (83).Chen CH; Palmer LC; Stupp SI Self-Repair of Structure and Bioactivity in a Supramolecular Nanostructure. Nano Lett. 2018, 18 (11), 6832–6841. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R84] (84).Anderson CF; Chakroun RW; Su H; Mitrut RE; Cui H Interface-Enrichment-Induced Instability and Drug-Loading-Enhanced Stability in Inhalable Delivery of Supramolecular Filaments. ACS Nano 2019, 13 (11), 12957–12968. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R85] (85).Park H; Park K Biocompatibility Issues of Implantable Drug Delivery Systems. Pharm. Res. 1996, 13 (12), 1770–1776. [DOI] [PubMed] [Google Scholar]

[R86] (86).Discher DE; Janmey P; Wang Y.-l. Tissue Cells Feel and Respond to the Stiffness of Their Substrate. Science 2005, 310 (5751), 1139. [DOI] [PubMed] [Google Scholar]

[R87] (87).Bellis SL Advantages of RGD peptides for directing cell association with biomaterials. Biomaterials 2011, 32 (18), 4205–4210. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R88] (88).Sugahara KN; Teesalu T; Karmali PP; Kotamraju VR; Agemy L; Greenwald DR; Ruoslahti E Coadministration of a Tumor-Penetrating Peptide Enhances the Efficacy of Cancer Drugs. Science 2010, 328 (5981), 1031. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R89] (89).Bradley KH; McConnell SD; Crystal RG Lung collagen composition and synthesis: Characterization and changes with age. J. Biol. Chem. 1974, 249 (9), 2674–2683. [PubMed] [Google Scholar]

[R90] (90).Anderson CF; Grimmett ME; Domalewski CJ; Cui H Inhalable nanotherapeutics to improve treatment efficacy for common lung diseases. WIREs Nanomed. Nanobiotechnol. 2020, 12 (1), e1586. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R91] (91).Lin R; Cheetham AG; Zhang P; Lin Y.-a.; Cui H Supramolecular filaments containing a fixed 41% paclitaxel loading. Chem. Commun. 2013, 49 (43), 4968–4970. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R92] (92).Dubikovskaya EA; Thorne SH; Pillow TH; Contag CH; Wender PA Overcoming multidrug resistance of small-molecule therapeutics through conjugation with releasable octaarginine transporters. Proc. Natl. Acad. Sci. U. S. A. 2008, 105 (34), 12128. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R93] (93).Cheetham AG; Zhang P; Lin Y.-a.; Lock LL; Cui H Supramolecular Nanostructures Formed by Anticancer Drug Assembly. J. Am. Chem. Soc. 2013, 135 (8), 2907–2910. [DOI] [PMC free article] [PubMed] [Google Scholar]

PERMALINK

Collagen-Binding Peptide-Enabled Supramolecular Hydrogel Design for Improved Organ Adhesion and Sprayable Therapeutic Delivery

Caleb F Anderson

Rami W Chakroun

Maria E Grimmett

Christopher J Domalewski

Feihu Wang

Honggang Cui

Abstract

Graphical Abstract