Graduation Semester and Year
Fall 2025
Language
English
Document Type
Dissertation
Degree Name
Doctor of Philosophy in Chemistry
Department
Chemistry and Biochemistry
First Advisor
He Dong
Abstract
pH-responsive supramolecular peptide-based biomaterials have emerged as a powerful class of functional materials due to their modular design, straightforward synthesis, and the ability to precisely tune their structural and physicochemical properties across multiple length scales. As part of this dissertation, I examine the systematic design, synthesis, and application of pH-responsive peptide materials, ranging from molecular-level approaches to bulk hydrogel systems, as well as their potential for antimicrobial therapy, drug delivery, and nucleic acid delivery.
Chapter 1 introduces the fundamental concepts of peptide self-assembly and stimuli-responsive systems, with an emphasis on pH-responsive supramolecular peptides. Key examples of peptide-based biomaterials are discussed, including their molecular design, structural characterization, and functional applications. Assemblies with trigger-responsive properties are discussed, emphasizing their applications in therapeutic delivery. In this chapter, pH responsiveness is framed as a powerful design principle for the development of precision biomaterials.
Chapter 2 details the rational design of pH-responsive peptides incorporating hydrophobic, ionizable non-natural amino acids. Novel synthetic strategies are presented for creating these amino acids and integrating them into peptide sequences. A combination of computational modeling and experimental approaches is used to investigate the assembly and disassembly of these peptides under different pH conditions. Additionally, these materials exhibit acidity-triggered antimicrobial activity, demonstrating their potential utility as a means of combating infections in pathologically acidic environments.
Chapter 3 builds upon this foundation by expanding the library of non-natural amino acids through systematic modulation of hydrophobicity and substitution patterns. By diversifying the design space, this work uncovers new insights into the structure-property relationships governing pH-responsive behavior. Characterization of these peptide assemblies reveals tunable and predictable disassembly mechanisms, providing a platform for tailoring functional responses in different biomedical contexts. This chapter underscores the novelty of constructing a broad, rationally designed library of ionizable amino acids as building blocks for pH-responsive biomaterials.
Chapter 4 addresses a fundamental limitation of peptide assemblies: their inability to form robust hydrogels due to low molecular weight and limited noncovalent interactions. To overcome this challenge, a new generalizable strategy is introduced in which β-sheet forming peptide nanofibers are chemically crosslinked with a 4-arm PEG polymer via NHS-amine click chemistry, yielding peptide-polymer double network hydrogels. These materials exhibit excellent injectability, self-healing capacity, and both biocompatibility and hemocompatibility. Their application in drug delivery is demonstrated, showcasing their potential as advanced biomedical scaffolds. The novelty of this approach lies in its adaptability, any lysine-terminated self-assembling peptide sequence can be used to form such hydrogels.
Chapter 5 extends this strategy by integrating pH responsiveness into peptide–polymer hydrogels through incorporation of the non-natural amino acid Xp. While the peptide alone is pH responsive but unable to form hydrogels, covalent crosslinking with PEG generates a robust material that is both mechanically strong and environmentally responsive. The hydrogel is used to encapsulate antimicrobial peptides, and acidity-triggered release studies confirm superior controlled release compared to non-responsive hydrogels. Additionally, encapsulation significantly reduces the inherent cytotoxicity of antimicrobial peptides, underscoring the therapeutic relevance of this platform. This represents a novel demonstration of combining pH-responsiveness with structural reinforcement in peptide–polymer hydrogels.
Chapter 6 introduces the design and synthesis of pH-responsive cell-penetrating peptides for nucleic acid delivery. By incorporating Xp into a previously reported cell-penetrating sequence, a dual-function material is created: the peptide self-assembles at neutral pH to transport nucleic acid cargo across the cell membrane and subsequently undergoes pH-triggered disassembly in the acidic endosomal environment to release the cargo. This chapter demonstrates how molecular-level design principles can be harnessed to solve a major challenge in drug delivery - achieving efficient endosomal escape.
Keywords
Peptide Self-assembly, pH-responsive, Antimicrobial therapy
Disciplines
Chemistry
License
This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 4.0 International License.
Recommended Citation
Asokan Sheeja, Haritha, "pH-Responsive Peptide Nanostructures Incorporating Non-Natural Amino Acids: Design, Self-Assembly, and Functional Evaluation" (2025). Chemistry & Biochemistry Dissertations. 291.
https://mavmatrix.uta.edu/chemistry_dissertations/291
Comments
Degree granted by The University of Texas at Arlington