N-Terminal Octylated Peptoid Hydrogels as 3D-Printable Cell Scaffolds and Proteolytically Robust Cargo Depots

Park, Il-Soo; Cho, Younghak; Lee, Yen Jea; Gutierrez, Daniela; Zuckermann, Ronald N.; Seong, Hyejeong; Kim, Jae Hong

doi:10.1021/acsnano.5c16998

N-Terminal Octylated Peptoid Hydrogels as 3D-Printable Cell Scaffolds and Proteolytically Robust Cargo Depots

Journal Article · Mon Feb 09 00:00:00 EST 2026 · ACS Nano

DOI:https://doi.org/10.1021/acsnano.5c16998· OSTI ID:3020777

Park, Il-Soo ^[1]; Cho, Younghak ^[1]; ^[2]; Gutierrez, Daniela ^[1]; ^[3]; ^[4]; ^[5]

Korea Institute of Science and Technology (KIST), Bucheon (Korea, Republic of)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States). Molecular Foundry
Korea Institute of Science and Technology (KIST), Bucheon (Korea, Republic of); University of Science and Technology, Seoul (Korea, Republic of)
Korea Institute of Science and Technology (KIST), Bucheon (Korea, Republic of); Gwangju Institute of Science and Technology (Korea, Republic of)

Supramolecular hydrogels that mimic the extracellular matrix (ECM) represent promising materials for tissue engineering and drug delivery. However, conventional hydrogels formed via the self-assembly of natural or synthetic building blocks often face a trade-off between biological functionality and biochemical stability, limiting their utility in long-term or protease-rich environments. Peptoids, a class of peptide-inspired, sequence-defined polymers, offer a compelling alternative due to their exceptional proteolytic resistance and bioactivity. Despite this potential, the development of supramolecular peptoid hydrogels has been hindered by the absence of backbone hydrogen bond donors, which limits long-range ordering necessary for efficient hydrogel formation. This work describes a short peptoid functionalized at the N-terminus with an octyl chain that readily self-assembles into hydrogels. Hydrophobic interactions among pendant octyl groups promote directional peptoid packing into highly ordered nanosheets, which interconnect to form a porous hydrogel network. These hydrogels exhibit tunable viscoelasticity, shear-thinning, and self-healing properties, enabling their use as inks for extrusion-based 3D printing. They support NIH-3T3 fibroblast adhesion, spreading, and proliferation, maintaining greater than 95% cell viability over 4 days. Moreover, the hydrogels retain their macroscopic integrity under protease-rich conditions, enabling sustained cargo release and uniform cellular uptake. Together, this study demonstrates a class of supramolecular peptoid hydrogelators that integrate biocompatibility, 3D printability, and proteolytic stability, providing a versatile platform for ECMmimetic scaffolds in regenerative medicine and long-term therapeutic delivery.

View Accepted Manuscript (DOE)

Research Organization:: US Department of Energy (USDOE), Washington, DC (United States). Office of Science, Basic Energy Sciences (BES)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 3020777

Journal Information:: ACS Nano, Journal Name: ACS Nano Journal Issue: 7 Vol. 20; ISSN 1936-086X; ISSN 1936-0851

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: English

References (65)

Extracellular Matrix‐Mimetic Immunomodulatory Hydrogel for Accelerating Wound Healing Wang, Honglei; Huang, Runzhi; Bai, Long Advanced Healthcare Materials, Vol. 12, Issue 27 https://doi.org/10.1002/adhm.202301264	journal	July 2023
Slip‐Stacked J‐Aggregate Materials for Organic Solar Cells and Photodetectors Kim, Jin Hong; Schembri, Tim; Bialas, David Advanced Materials, Vol. 34, Issue 22 https://doi.org/10.1002/adma.202104678	journal	October 2021
3D Printing of Self‐Assembling Nanofibrous Multidomain Peptide Hydrogels Farsheed, Adam C.; Thomas, Adam J.; Pogostin, Brett H. Advanced Materials https://doi.org/10.1002/adma.202210378	journal	January 2023
Propelling Minimally Invasive Tissue Regeneration With Next‐Era Injectable Pre‐Formed Scaffolds Liao, Junhan; Timoshenko, Anastasia B.; Cordova, Domenic J. Advanced Materials, Vol. 36, Issue 33 https://doi.org/10.1002/adma.202400700	journal	June 2024
Self‐Assembly of Aggregation‐Induced‐Emission Molecules Wu, Tongyue; Huang, Jianbin; Yan, Yun Chemistry – An Asian Journal, Vol. 14, Issue 6 https://doi.org/10.1002/asia.201801884	journal	March 2019
The effect of the size of fluorescent dextran on its endocytic pathway Li, Lei; Wan, Tao; Wan, Min Cell Biology International, Vol. 39, Issue 5 https://doi.org/10.1002/cbin.10424	journal	January 2015
Control of H- and J-Type π Stacking by Peripheral Alkyl Chains and Self-Sorting Phenomena in Perylene Bisimide Homo- and Heteroaggregates Ghosh, Suhrit; Li, Xue-Qing; Stepanenko, Vladimir Chemistry - A European Journal, Vol. 14, Issue 36 https://doi.org/10.1002/chem.200801454	journal	November 2008
Biodegradable, ionic thermoelectric composites via self-assembly of dipeptides and deep eutectic solvents Yang, Woojin; Park, Minju; Choi, Yoohyeon Advanced Composites and Hybrid Materials, Vol. 8, Issue 1 https://doi.org/10.1007/s42114-025-01239-8	journal	January 2025
Proteolytic studies of homologous peptide and N-substituted glycine peptoid oligomers Miller, Susan M.; Simon, Reyna J.; Ng, Simon Bioorganic & Medicinal Chemistry Letters, Vol. 4, Issue 22 https://doi.org/10.1016/S0960-894X(01)80691-0	journal	November 1994
Peptide and peptide-carbon nanotube hydrogels as scaffolds for tissue & 3D tumor engineering Sheikholeslam, Mohammadali; Wheeler, Scott D.; Duke, Keely G. Acta Biomaterialia, Vol. 69 https://doi.org/10.1016/j.actbio.2017.12.012	journal	March 2018
Intelligent biobased hydrogels for diabetic wound healing: A review Wang, Hanzhang; Zhang, Li-Ming Chemical Engineering Journal, Vol. 484 https://doi.org/10.1016/j.cej.2024.149493	journal	March 2024
Hydrogels mimicking the viscoelasticity of extracellular matrix for regenerative medicine: Design, application, and molecular mechanism Li, Lichen; Wang, Shuhan; Chen, You Chemical Engineering Journal, Vol. 498 https://doi.org/10.1016/j.cej.2024.155206	journal	October 2024
Protein aggregation and its inhibition in biopharmaceutics Wang, Wei International Journal of Pharmaceutics, Vol. 289, Issue 1-2 https://doi.org/10.1016/j.ijpharm.2004.11.014	journal	January 2005
Higuchi equation: Derivation, applications, use and misuse Siepmann, Juergen; Peppas, Nicholas A. International Journal of Pharmaceutics, Vol. 418, Issue 1 https://doi.org/10.1016/j.ijpharm.2011.03.051	journal	October 2011
Supramolecular Assembly of Peptide Amphiphiles Hendricks, Mark P.; Sato, Kohei; Palmer, Liam C. Accounts of Chemical Research, Vol. 50, Issue 10 https://doi.org/10.1021/acs.accounts.7b00297	journal	September 2017
Self-Assembly and Cytocompatibility of Amino Acid Conjugates Containing a Novel Water-Soluble Aromatic Protecting Group Castelletto, Valeria; de Mello, Lucas; da Silva, Emerson Rodrigo Biomacromolecules, Vol. 24, Issue 11 https://doi.org/10.1021/acs.biomac.3c00860	journal	November 2023
Permselectivity of Silk Fibroin Hydrogels for Advanced Drug Delivery Neurotherapies Fernández-Serra, Rocío; Lekouaghet, Amira; Peracho, Lorena Biomacromolecules, Vol. 25, Issue 8 https://doi.org/10.1021/acs.biomac.4c00629	journal	July 2024
Printability and Shape Fidelity of Bioinks in 3D Bioprinting Schwab, Andrea; Levato, Riccardo; D’Este, Matteo Chemical Reviews, Vol. 120, Issue 19 https://doi.org/10.1021/acs.chemrev.0c00084	journal	August 2020
Hierarchical Nanomaterials Assembled from Peptoids and Other Sequence-Defined Synthetic Polymers Li, Zhiliang; Cai, Bin; Yang, Wenchao Chemical Reviews, Vol. 121, Issue 22 https://doi.org/10.1021/acs.chemrev.1c00024	journal	August 2021
Self-Healing Injectable Hydrogels for Tissue Regeneration Bertsch, Pascal; Diba, Mani; Mooney, David J. Chemical Reviews, Vol. 123, Issue 2 https://doi.org/10.1021/acs.chemrev.2c00179	journal	August 2022
Aggregation-Induced Emission: Together We Shine, United We Soar! Mei, Ju; Leung, Nelson L. C.; Kwok, Ryan T. K. Chemical Reviews, Vol. 115, Issue 21 https://doi.org/10.1021/acs.chemrev.5b00263	journal	October 2015
Supramolecular Hydrogelators and Hydrogels: From Soft Matter to Molecular Biomaterials Du, Xuewen; Zhou, Jie; Shi, Junfeng Chemical Reviews, Vol. 115, Issue 24 https://doi.org/10.1021/acs.chemrev.5b00299	journal	December 2015
Phase Transition from the Interdigitated to Bilayer Membrane of a Cationic Surfactant Induced by Addition of Hydrophobic Molecules Hishida, Mafumi; Shimokawa, Naofumi; Okubo, Yuki Langmuir, Vol. 36, Issue 48 https://doi.org/10.1021/acs.langmuir.0c02609	journal	November 2020
Peptide Assembly of Different Dimensions and Their Effect on Myoblast Proliferation Hong, Jinwoo; Kim, Taeyeon; Kim, Jehan ACS Applied Materials & Interfaces, Vol. 15, Issue 25 https://doi.org/10.1021/acsami.3c01482	journal	June 2023
Self-Assembly of Minimal Peptoid Sequences Castelletto, Valeria; Seitsonen, Jani; Tewari, Kunal M. ACS Macro Letters, Vol. 9, Issue 4 https://doi.org/10.1021/acsmacrolett.9b01010	journal	March 2020
Hierarchical Approach for Controlled Assembly of Branched Nanostructures from One Polymer Compound by Engineering Crystalline Domains Ding, Xiangmin; Liu, Dandan; Jiang, Xi ACS Nano, Vol. 16, Issue 7 https://doi.org/10.1021/acsnano.2c01171	journal	May 2022
Self-Assembling and Pore-Forming Peptoids as Antimicrobial Biomaterials Jian, Tengyue; Wang, Minghui; Hettige, Jeevapani ACS Nano, Vol. 18, Issue 34 https://doi.org/10.1021/acsnano.4c05250	journal	August 2024
Efficient method for the preparation of peptoids [oligo(N-substituted glycines)] by submonomer solid-phase synthesis Zuckermann, Ronald N.; Kerr, Janice M.; Kent, Stephen B. H. Journal of the American Chemical Society, Vol. 114, Issue 26 https://doi.org/10.1021/ja00052a076	journal	December 1992
Two-Dimensional Peptide Assembly via Arene–Perfluoroarene Interactions for Proliferation and Differentiation of Myoblasts Kim, Taeyeon; Hong, Jinwoo; Kim, Jehan Journal of the American Chemical Society, Vol. 145, Issue 3 https://doi.org/10.1021/jacs.2c10938	journal	January 2023
In Situ Forming, Enzyme-Responsive Peptoid-Peptide Hydrogels: An Advanced Long-Acting Injectable Drug Delivery System Coulter, Sophie M.; Pentlavalli, Sreekanth; An, Yuming Journal of the American Chemical Society, Vol. 146, Issue 31 https://doi.org/10.1021/jacs.4c03751	journal	June 2024
Universal Relationship between Molecular Structure and Crystal Structure in Peptoid Polymers and Prevalence of the cis Backbone Conformation Greer, Douglas R.; Stolberg, Michael A.; Kundu, Joyjit Journal of the American Chemical Society, Vol. 140, Issue 2 https://doi.org/10.1021/jacs.7b11891	journal	January 2018
Supramolecular Structures of J-Aggregates of Carbocyanine Dyes in Solution von Berlepsch, H.; Böttcher, C.; Ouart, A. The Journal of Physical Chemistry B, Vol. 104, Issue 22 https://doi.org/10.1021/jp000220z	journal	May 2000
Blue Luminescence Based on Quantum Confinement at Peptide Nanotubes Amdursky, Nadav; Molotskii, Michel; Aronov, Daniel Nano Letters, Vol. 9, Issue 9 https://doi.org/10.1021/nl9008265	journal	August 2009
Peptoid Polymers: A Highly Designable Bioinspired Material Sun, Jing; Zuckermann, Ronald N. ACS Nano, Vol. 7, Issue 6 https://doi.org/10.1021/nn4015714	journal	May 2013
Designing hydrogels for controlled drug delivery Li, Jianyu; Mooney, David J. Nature Reviews Materials, Vol. 1, Issue 12 https://doi.org/10.1038/natrevmats.2016.71	journal	October 2016
Role of the extracellular matrix in regulating stem cell fate Watt, Fiona M.; Huck, Wilhelm T. S. Nature Reviews Molecular Cell Biology, Vol. 14, Issue 8 https://doi.org/10.1038/nrm3620	journal	July 2013
Remodelling the extracellular matrix in development and disease Bonnans, Caroline; Chou, Jonathan; Werb, Zena Nature Reviews Molecular Cell Biology, Vol. 15, Issue 12 https://doi.org/10.1038/nrm3904	journal	November 2014
Design of Peptoid-peptide Macrocycles to Inhibit the β-catenin TCF Interaction in Prostate Cancer Schneider, Jeffrey A.; Craven, Timothy W.; Kasper, Amanda C. Nature Communications, Vol. 9, Issue 1 https://doi.org/10.1038/s41467-018-06845-3	journal	October 2018
Concepts of extracellular matrix remodelling in tumour progression and metastasis Winkler, Juliane; Abisoye-Ogunniyan, Abisola; Metcalf, Kevin J. Nature Communications, Vol. 11, Issue 1 https://doi.org/10.1038/s41467-020-18794-x	journal	October 2020
Control cell migration by engineering integrin ligand assembly Hu, Xunwu; Roy, Sona Rani; Jin, Chengzhi Nature Communications, Vol. 13, Issue 1 https://doi.org/10.1038/s41467-022-32686-2	journal	August 2022
Assembly of short amphiphilic peptoids into nanohelices with controllable supramolecular chirality Zheng, Renyu; Zhao, Mingfei; Du, Jingshan S. Nature Communications, Vol. 15, Issue 1 https://doi.org/10.1038/s41467-024-46839-y	journal	April 2024
Controlling supramolecular gels Draper, Emily R.; Adams, Dave J. Nature Materials, Vol. 23, Issue 1 https://doi.org/10.1038/s41563-023-01765-0	journal	January 2024
Lipopeptides as tools in catalysis, supramolecular, materials and medicinal chemistry Vicente-Garcia, Cesar; Colomer, Ignacio Nature Reviews Chemistry, Vol. 7, Issue 10 https://doi.org/10.1038/s41570-023-00532-8	journal	September 2023
Cell–extracellular matrix mechanotransduction in 3D Saraswathibhatla, Aashrith; Indana, Dhiraj; Chaudhuri, Ovijit Nature Reviews Molecular Cell Biology, Vol. 24, Issue 7 https://doi.org/10.1038/s41580-023-00583-1	journal	February 2023
Mechanisms of assembly and remodelling of the extracellular matrix Naba, Alexandra Nature Reviews Molecular Cell Biology, Vol. 25, Issue 11 https://doi.org/10.1038/s41580-024-00767-3	journal	September 2024
Organoids Zhao, Zixuan; Chen, Xinyi; Dowbaj, Anna M. Nature Reviews Methods Primers, Vol. 2, Issue 1 https://doi.org/10.1038/s43586-022-00174-y	journal	December 2022
Dissolution and degradation of Fmoc-diphenylalanine self-assembled gels results in necrosis at high concentrations in vitro Truong, Warren Ty; Su, Yingying; Gloria, Danmar Biomaterials Science, Vol. 3, Issue 2 https://doi.org/10.1039/C4BM00244J	journal	January 2015
Shape effect in cellular uptake of PEGylated nanoparticles: comparison between sphere, rod, cube and disk Li, Ying; Kröger, Martin; Liu, Wing Kam Nanoscale, Vol. 7, Issue 40 https://doi.org/10.1039/C5NR02970H	journal	January 2015
Exploring the links between peptoid antibacterial activity and toxicity Bolt, H. L.; Eggimann, G. A.; Jahoda, C. A. B. MedChemComm, Vol. 8, Issue 5 https://doi.org/10.1039/C6MD00648E	journal	January 2017
Controlling the width of nanosheets by peptide length in peptoid–peptide biohybrid hydrogels Ren, Xinrui; Yang, Chengbiao; Li, Can RSC Advances, Vol. 6, Issue 71 https://doi.org/10.1039/C6RA15291K	journal	January 2016
Diblock copolypeptoids: a review of phase separation, crystallization, self-assembly and biological applications Xuan, Sunting; Zuckermann, Ronald N. Journal of Materials Chemistry B, Vol. 8, Issue 25 https://doi.org/10.1039/D0TB00477D	journal	January 2020
Protein-mimetic peptoid nanoarchitectures for pathogen recognition and neutralization Yang, Woojin; Seo, Jiwon; Kim, Jae Hong Nanoscale, Vol. 15, Issue 3 https://doi.org/10.1039/D2NR05326H	journal	January 2023
Molecular hydrogelators of peptoid–peptide conjugates with superior stability against enzyme digestion Wu, Zhidan; Tan, Ming; Chen, Xuemei Nanoscale, Vol. 4, Issue 12 https://doi.org/10.1039/c2nr30408b	journal	January 2012
Role of target geometry in phagocytosis Champion, J. A.; Mitragotri, S. Proceedings of the National Academy of Sciences, Vol. 103, Issue 13 https://doi.org/10.1073/pnas.0600997103	journal	March 2006
Peptoids that mimic the structure, function, and mechanism of helical antimicrobial peptides Chongsiriwatana, N. P.; Patch, J. A.; Czyzewski, A. M. Proceedings of the National Academy of Sciences, Vol. 105, Issue 8 https://doi.org/10.1073/pnas.0708254105	journal	February 2008
Biomimetic peptoid oligomers as dual-action antifreeze agents Huang, M. L.; Ehre, D.; Jiang, Q. Proceedings of the National Academy of Sciences, Vol. 109, Issue 49 https://doi.org/10.1073/pnas.1212826109	journal	November 2012
Hierarchical supramolecular assembly of a single peptoid polymer into a planar nanobrush with two distinct molecular packing motifs Sun, Jing; Wang, Zhiwei; Zhu, Chenhui Proceedings of the National Academy of Sciences, Vol. 117, Issue 50 https://doi.org/10.1073/pnas.2011816117	journal	December 2020
Viscoelastic Biomaterials for Tissue Regeneration Wu, David T.; Jeffreys, Nicholas; Diba, Mani Tissue Engineering Part C: Methods, Vol. 28, Issue 7 https://doi.org/10.1089/ten.tec.2022.0040	journal	July 2022
Growth Factors, Matrices, and Forces Combine and Control Stem Cells Discher, D. E.; Mooney, D. J.; Zandstra, P. W. Science, Vol. 324, Issue 5935 https://doi.org/10.1126/science.1171643	journal	June 2009
Allergen-induced IL-9 directly stimulates mucin transcription in respiratory epithelial cells Longphre, M.; Li, D.; Gallup, M. Journal of Clinical Investigation, Vol. 104, Issue 10 https://doi.org/10.1172/JCI6097	journal	November 1999
Controlling supramolecular filament chirality of hydrogel by co-assembly of enantiomeric aromatic peptides Yang, Xuejiao; Lu, Honglei; Tao, Yinghua Journal of Nanobiotechnology, Vol. 20, Issue 1 https://doi.org/10.1186/s12951-022-01285-0	journal	February 2022
The extracellular matrix at a glance Frantz, C.; Stewart, K. M.; Weaver, V. M. Journal of Cell Science, Vol. 123, Issue 24 https://doi.org/10.1242/jcs.023820	journal	December 2010
An update on the use of degarelix in the treatment of advanced hormone-dependent prostate cancer Rick, Ferenc; Schally, Andrew OncoTargets and Therapy https://doi.org/10.2147/OTT.S32426	journal	April 2013
Targeted Drug Delivery via the Use of ECM-Mimetic Materials Hwang, Jeongmin; Sullivan, Millicent O.; Kiick, Kristi L. Frontiers in Bioengineering and Biotechnology, Vol. 8 https://doi.org/10.3389/fbioe.2020.00069	journal	February 2020
Metalloporphyrin Dimers Bridged by a Peptoid Helix: Host-Guest Interaction and Chiral Recognition Lee, Yen; Kang, Boyeong; Seo, Jiwon Molecules, Vol. 23, Issue 11 https://doi.org/10.3390/molecules23112741	journal	October 2018

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