Nanofibrous supramolecular peptide hydrogels for controlled release of small-molecule drugs and biologics

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Nanofibrous supramolecular peptide hydrogels for controlled release of small-molecule drugs and biologics

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The authors declare that all the data supporting the findings of this research are available within the article and its Supplementary Information. Source data are available upon reasonable request. Source data are provided with this paper.

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Acknowledgements

We would like to acknowledge U. Olsson and the Olsson laboratory for their hospitality at Lund University and C. Hetherington for capturing cryo-TEM images. We recognize F. Lerner for assistance synthesizing an SHA starting material compatible with solid-phase peptide synthesis, G. Saenz for his assistance with peptide synthesis, H. Kandry for guidance with pharmacokinetic analyses, A. J. Budi Utama for help developing a protocol for fluorescence recovery after photobleaching and A. Torres for help copy editing. We would like to further acknowledge N. Dharmaraj, N. Hussein, S. Young and A. Sikora for their support and advice throughout the project. B.H.P. received funding from the NSF Graduate Student Research Fellowship programme and the National Cancer Institute F99/K00 programme (award number F99CA284262). Mass spectrometry imaging was performed in the UT Austin Mass Spectrometry Imaging Facility supported by Cancer Prevention and Research Institute of Texas award RP190617 (E.H.S.). This project was supported in part with NIH grants R35GM143101 (K.J.M.), R01DE021798 (J.D.H.), R01DE030140 (J.D.H.) and R61-AI-161809 (E.L.N.). We acknowledge support from the Welch Foundation (Research Grant C-1680, J.D.H.), the National Science Foundation (CHE-2203948, Z.T.B.) and the Cancer Prevention and Research Institute of Texas (RR190056, K.J.M.).

Author information

Authors and Affiliations

  1. Department of Bioengineering, Rice University, Houston, TX, USA

    Brett H. Pogostin, Samuel X. Wu, Dilrasbonu Vohidova, Anushka Agrawal, Chaoyang Tang, Marina H. Yu, Jacob Cabler, Omid Veiseh, Jeffrey D. Hartgerink & Kevin J. McHugh

  2. Department of Chemistry, Rice University, Houston, TX, USA

    Michael J. Swierczynski, Arghadip Dey, Zachary T. Ball, Jeffrey D. Hartgerink & Kevin J. McHugh

  3. Shared Equipment Authority, Rice University, Houston, TX, USA

    Christopher Pennington

  4. Center for Tuberculosis Research, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Si-Yang Li & Eric L. Nuermberger

  5. Department of Chemistry, University of Texas at Austin, Austin, TX, USA

    Erin H. Seeley

  6. Department of Chemical and Biomolecular Engineering, Rice University, Houston, TX, USA

    Sofia Hernandez

Authors

  1. Brett H. Pogostin
  2. Samuel X. Wu
  3. Michael J. Swierczynski
  4. Christopher Pennington
  5. Si-Yang Li
  6. Dilrasbonu Vohidova
  7. Erin H. Seeley
  8. Anushka Agrawal
  9. Chaoyang Tang
  10. Marina H. Yu
  11. Arghadip Dey
  12. Sofia Hernandez
  13. Jacob Cabler
  14. Omid Veiseh
  15. Eric L. Nuermberger
  16. Zachary T. Ball
  17. Jeffrey D. Hartgerink
  18. Kevin J. McHugh

Contributions

B.H.P., J.D.H. and K.J.M. conceptualized and designed the study. B.H.P. and M.J.S. designed the peptide materials. B.H.P., S.X.W., M.J.S., C.T., A.D., A.A. and S.H. synthesized the materials. B.H.P., S.X.W., C.T. and A.D. conducted the in vitro release experiments. B.H.P. and S.X.W. performed other in vitro characterizations of the materials. B.H.P., S.X.W. and C.P. conducted the mass spectrometry pharmacokinetics experiments using methods that C.P. developed. B.H.P. performed the non-compartmental pharmacokinetic analysis on the data. S.-Y.L. conducted the tuberculosis experiments that E.L.N. designed. B.H.P. and A.A. performed the fluorescence recovery after photobleaching and in vivo imaging experiments. B.H.P., D.V. and J.C. collected the data for diabetes experiments that O.V. designed. B.H.P. and E.H.S. performed the mass spectrometry imaging experiments using methods that E.H.S. developed. M.H.Y. collected the histology data. Z.T.B., J.D.H. and K.J.M. supervised the project.

Corresponding authors

Correspondence to Jeffrey D. Hartgerink or Kevin J. McHugh.

Ethics declarations

Competing interests

B.H.P., M.J.S., Z.T.B., J.D.H. and K.J.M. are co-inventors on a patent related to dynamic covalent bonding to MDPs described here. K.J.M. has received research funding support from Nanocan Therapeutics and serves as a paid consultant for the company. His work in those roles is unrelated to the content described herein. E.L.N. and S-.Y.L. received research funding support from Janssen in the past 2 years. The remaining authors declare no competing interests.

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Nature Nanotechnology thanks Alessandro Gori, Kristopher Kilian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Extended data

Extended Data Fig. 1 Design and development of SABER peptides.

a) Catechol oxidation and degradation occurred rapidly, appearing as changes in the UV-Vis spectrum of dopamine (DOPA) over time in pH 7.4 PBS. The increase in the baseline absorbance indicates increased turbidity of the sample as insoluble oxidation products form black precipitates in solution. b) The UV-Vis spectrum of the nitrocatechol 4-nitrodopamine (nDOPA) shows that the molecule is stable over the course of 15 d. c) Longitudinal analysis of the UV-Vis spectrum salicylhydroxamic acid (SHA) demonstrates that the molecule is largely stable with minor changes observed after 11 d. d) Boronate ester equilibrium constants between chemically distinct boronic acids (BAs) and the dynamic covalent association motifs alizarin red S (ARS), nDOPA, SHA, and DOPA. For all BAs, SHA forms the strongest boronate ester interactions. Equilibrium constants are presented as the mean value of three replicates ± SD (see Supplementary Fig. S1). e-f) Chemical structures, mass spectra, and UPLC chromatograms of e) Cat-K2, f) nitroCat-K2, g) SHA-K2, and h) K2.

Source data

Extended Data Fig. 2 In vitro release and drug stability.

a) Cumulative release of bortezomib from SHA-K2 is not significantly altered within physiologically relevant concentrations of glucose. b) The total amount of bortezomib released after 24 h was not statistically different between glucose concentrations. Data are presented as the mean value of three replicates ± SD. c) Gels loaded with drug were dissolved in water and run on UPLC to ensure that all of the drug could be recovered. Bars with ‘#’ reached 100% release in the release experiments shown in Fig. 2 and cumulative release from those experiments after 24 h is shown here. These data demonstrate that all the drug loaded into the gels can be released. Data are presented as the mean value of three replicates ± SD. d) The change in UPLC retention time of ganfeborole and ganfeborole released from Cat-K2 in UPLC suggests that the hydrogel is degrading the drug. The new peak at 3.2 min seen in Cat-K2 + ganfeborole is also observed when the drug is reacted with 280 mM hydrogen peroxide, suggesting that this new peak corresponds to oxidized ganfeborole. e) Electrospray ionization mass spectrometry of ganfeborole alone contains the expected mass of the drug at 258.1 m/z. Ganfeborole released from Cat-K2 has a peak at 248.1 m/z, (f) corresponding to a loss of a boron atom due to oxidative deboronation. g) The stability of ganfeborole loaded in K2, Cat-K2, nitroCat-K2, and SHA-K2 quantified by UPLC shows that the majority of the drug remains stable over the course of two weeks in all hydrogels except for Cat-K2, which rapidly degrades the compound. Data are presented as the mean value of three replicates ± SD. h) SHA-K2 without drug and the hydrogel maximally loaded (1:1 drug-to-peptide molar ratio) have the same β-sheet secondary structure as determined by a minimum at 220 nm seen by circular dichroism, suggesting that drug loading does not perturb peptide self-assembly.

Source data

Extended Data Fig. 3 In vitro release of fluorescent BAs.

a) Structures of fluorescein and the six fluorescein BA conjugates synthesized. b) In vitro release of the fluorescent BAs from SHA-K2 over the course of 336 h. All BA-modified compounds demonstrate significantly lower release than unmodified fluorescein. c) A rescaled release curve focusing on the six BA-modified compounds. The higher burst release observed in compound 6 may be due to the presence of a small amount of unconjugated fluorescein. The compounds demonstrate zero-order ‘linear’ release from 72–336 h. d) The linear release regime for each sample was fit to a line to calculate the release rate. All fits resulted in an R2 > 0.97. Compound 5 demonstrated the fastest release rate, which is over two-fold faster than the slowest releasing compounds (2, 4, and 6). These data demonstrate that minor changes to BA structure can impact the release rate from SABER hydrogels. All data is presented as the mean value of three replicates ± SD.

Source data

Extended Data Fig. 4 In vivo release of bortezomib.

a) Pharmacokinetics of decreasing bortezomib doses administered as subcutaneous boluses without hydrogel. Data is presented as the mean value of four replicates ± SEM. b) The maximum circulating concentration (Cmax) of bortezomib decreases linearly with the initial dose. Dotted lines represent the Cmax for 700 ng of bortezomib delivered from nitroCat-K2 (blue) and SHA-K2 (purple), indicating that a bolus bortezomib dose of 175 ng yields the same Cmax as these hydrogel formulations loaded with 5-fold more drug. c) Chemical structure of the bortezomib fragment observed in mass spectrometry imaging. d) K2, nitroCat-K2, and SHA-K2 hydrogels loaded with 700 ng of bortezomib imaged by mass spectrometry imaging in vitro show very little bortezomib signal, suggesting that MDP peptides suppress the ionization of bortezomib within the gels. This ionization suppression results in dark spots in mass spectrometry images at the location of the hydrogels.

Source data

Extended Data Fig. 5 Hematoxylin & eosin staining and mass spectrometry imaging of injection site tissues.

a) Tissue sections from mice that received subcutaneous injections of bortezomib alone or in a hydrogel at 1-, 7-, and 21-days stained with hematoxylin & eosin. Large dark purple sections in K2, nitroCat-K2, and SHA-K2 are the hydrogels in the skin samples. b) Mass spectrometry imaging of the same tissue samples stained with hematoxylin & eosin shows that bortezomib signal does not significantly overlap with that from heme (616.178 m/z), illustrating that the drug observed in the tissue is not in circulation but in the local environment of the injection site.

Extended Data Fig. 6 Pharmacokinetics of ganfeborole in 50 μL of 10 mg/mL hydrogels.

Longitudinal concentrations of ganfeborole in the blood of mice after a single subcutaneous injection of 75 μg of the drug loaded into 50 μL hydrogels or PBS. Data presented as the mean value of four replicates ± SEM. Injections of ganfeborole without a hydrogel, ganfeborole in K2, and ganfeborole in nitroCat-K2 all led to the rapid release of the drug. SHA-K2 hydrogels were able to retain ganfeborole concentrations over the EC50 for more than 200 h.

Source data

Extended Data Fig. 7 In vitro characterization of SHA-E2 and in vivo release of ganfeborole.

a) Chemical structure of SHA-E2 with the mass spectrum and UPLC chromatogram of the material confirming the identity and purity of the peptide. b) Mass spectrum and UPLC chromatogram of the unmodified E2 peptide. c) Frequency sweep collected by oscillatory rheology shows that SHA-E2 hydrogels are more frequency dependent than unmodified E2 and form slightly weaker gels, as indicated by a reduction in the difference between the storage modulus (G′), indicated by filled circles and solid lines, and the loss modulus (G″), indicated by open circles and dotted lines. d) Representative histological sections of SHA-K2 and SHA-E2 gels excised three days after subcutaneous injection. Sections were stained with hematoxylin & eosin (left two images) or Masson’s trichrome (right four images) stains. Black 750 μm scale bar applies to the left four full sized images. Histological analysis shows that SHA-K2 gels swell significantly and are heavily infiltrated by cells, consistent with an inflammatory response. SHA-E2 remains minimally infiltrated by cells, has less collagen deposition on the border of the gel, and does not swell in size. e) Cumulative release of ganfeborole after 24 h from SHA-K2 and SHA-E2 are statistically similar, suggesting that changing the peptide used in SABER hydrogels does not compromise its ability to control the release of BA-containing small molecules. Data is presented as the mean of three replicates ± SD. f) Pharmacokinetic parameters extracted by performing a non-compartmental analysis on the in vivo release of ganfeborole from SHA-E2 show that using the SABER hydrogel improves drug exposure (AUC), half-life (t1/2) and reduces the maximum circulating concentration (Cmax) of the compound. Pharmacokinetic parameters are presented as the mean of n=4-5 replicates ± SD.

Source data

Extended Data Fig. 8 Local release of BA-modified IgG.

a) Representative confocal images illustrating fluorescence recovery and photobleaching (FRAP) experiments. Fluorescence recovery was quantified by monitoring the return of fluorescence signal in the bleached region over 10 min using a 640 nm excitation laser. The white scale bar in the bottom left represents 40 μm. b) FRAP data (n=3 for each group) was fit to a first-order exponential equation to extract the FRAP half-time (t1/2) and the mobile fraction (Mf). Loading BA-modified IgG in SABER hydrogels reduced the Mf and increased the t1/2, suggesting that the rate of payload diffusion in these samples is slower. We observed minimal differences between IgG labeled with 11.4 BAs per antibody (IgG high) and 2.4 BAs per antibody (IgG low), demonstrating that the degree of labeling may not play a large role in controlling the rate of diffusion. All data were well-modeled by the first-order exponential equation and had R2 values above 0.95 except for SHA-E2 + IgG high (denoted with an asterisk), which was poorly fit by this model and thus extracted parameters may not accurately describe the data. c) In vivo release data of IgG with low and high degrees of BA modeling was modeled with a first-order exponential equation to determine the half-life (t1/2) and burst release from the site of injection. All SABER hydrogels had a moderate burst release of 20% but significantly extended the t1/2 of the antibody at the injection site. All fits adequately modeled the data (R2 > 0.95). All numerical data in this figure is presented as the mean value of four replicates ± 95% confidence interval.

Extended Data Fig. 9 Basal insulin delivery from SABER hydrogels.

a) Mass spectrum of BA-modified insulin (insulin-PBA) showing that a single phenylboronic acid was added to insulin. b) The UPLC chromatogram of the synthesized insulin-PBA confirmed the purity of the material. c) In vitro release of unmodified insulin from SHA-E2 and E2 illustrates that the phenylboronic acid modification is necessary for the SABER peptide to achieve the delay in the release of the payload observed in Fig. 6a. Data presented as the mean value of three replicates ± SD. d) First 10 h of the initial treatment of diabetic mice with 6 IU of insulin-PBA in SHA-E2 plotted with a repeat treatment with the same formulation in the same mice 6 weeks later. The repeat dose resulted in statistically similar blood glucose levels to the initial dose at all time points. Data points for blood glucose measurements are the mean value of five replicates ± SEM.

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Pogostin, B.H., Wu, S.X., Swierczynski, M.J. et al. Nanofibrous supramolecular peptide hydrogels for controlled release of small-molecule drugs and biologics. Nat. Nanotechnol. (2025). https://doi.org/10.1038/s41565-025-01981-6

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  • DOI: https://doi.org/10.1038/s41565-025-01981-6