Due to their varied amino acid sequences and predictable conformational properties, peptides play a crucial role in bioorganic and supramolecular chemistry. They comprise of amino acid subunits linked by peptide bonds and form primary and secondary structures. The first synthetic peptide, glycylglycine, was synthesized in 1901, signifying the inception of peptide chemistry. Since then, this field has witnessed enormous progress, making important contributions in the broad area of functional biomolecules(Fischer et al., 1906).

The phenomenon of amyloidosis entails the misfolding of soluble proteins, leading to their aggregation into supramolecular assemblies characterised by β-structures. These aggregations occur due to specific motifs and are particularly observed within the central nervous system (CNS), though correlations have also been found in other critical organs such as the blood, gut, heart, kidney, muscle, and liver(Avila et al., 2023). These assembled proteins eventually accumulate in various organs, leading to over 30 types of diseases, including type II diabetes and neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's disease(Hajipour et al., 2017; Lai et al., 2021).

Amyloid is a term for protein aggregates with standard features such as fibrillar shape, β-sheet structure, birefringence with Congo red, insolubility, and protease resistance. Huntington's, Alzheimer's, and spongiform encephalopathy diseases share insoluble protein aggregates near the affected tissue. Alzheimer's disease is characterised by the presence of senile plaques(Singh et al., 2023), which are extracellular deposits of beta-amyloid peptide fibrils surrounded by degenerating neurites(Barage and Sonawane, 2015; Murphy, 2002; Pikuleva, 2021). Lewy bodies, observed in Parkinson's patients, consist mainly of amyloid-like fibrils of α-synuclein. Mutant forms of α-synuclein, such as A53T, A30P, and E46K, accelerate the aggregation and fibrillation of α-synuclein, leading to autosomal-dominant Parkinson's disease. These findings strongly support the idea that α-synuclein serves as the pathogenic protein in Parkinson's disease(Gadhe et al., 2022).

Self-assembly is a spontaneous bottom-up process in which the disordered components interact to form organised structures(Boncheva and Whitesides, 2005). It commences with nucleation, triggering the development of ordered structures ranging from organic crystals to macromolecules(Whitesides and Grzybowski, 2002). In bio-nanotechnology, self-assembly results in various structures, such as lipid micelles, DNA helices, lipid bilayers, and complex protein formations. While DNA and lipids form predictable and functional nanostructures. Proteins offer a higher level of complexity and functionality, particularly in creating three-dimensional architectures(McLaughlin et al., 2011).

Peptide assembly is a spontaneous thermodynamically driven process(J. Wang et al., 2016). The synergistic effect of different non-covalent interactions, including hydrogen-bonding, π–π stacking, electrostatic, hydrophobic, and van der Waals interactions, determine the thermodynamic stability of the nanostructures formed(J. Wang et al., 2016). Molecular interactions that govern the aggregation process are fundamentally influenced by various thermodynamic parameters. Key among these is Gibbs free energy, which dictates the spontaneity of the aggregation, along with enthalpy and entropy, which contribute to the overall stability and favorability of the interaction. Additionally, the heat capacity at constant pressure plays a crucial role in characterizing how the system's energy changes with temperature, further impacting the aggregation behaviour of molecules. The formation of amyloid fibrils is often associated with negative heat capacity, ΔC_p (Ikenoue et al., 2014). This value of negative ΔC_p indicates that the hydrophobic interactions play a significant role in self-assembly and is closely linked to the hydrophobic surface area, buried during the self-assembly of structures or fibrils (Ikenoue et al., 2014; Marsh, 2012). It also establishes a temperature-dependent relationship between enthalpy and entropy, which influences the stability of amyloid fibrils (Ikenoue et al., 2014). At lower temperatures, self-assembly is primarily driven by a favorable entropy, while at higher temperatures, it is governed by a favorable enthalpy (Ikenoue et al., 2014). These factors collectively inform our understanding of the thermodynamics underlying molecular aggregation processes (Sato et al., 2022).

This review provides a comprehensive analysis of the multifaceted factors that govern peptide self-assembly. Key elements scrutinized include the peptide sequence, concentration, and environmental parameters such as pH and temperature, as well as the influence of co-solvents. Each of these factors significantly impacts the stability and aggregation of peptide structures, contributing to the complexity of the self-assembly. Additionally, the review explores therapeutic strategies that can modulate the dynamics of self-assembly, drawing on the principles of thermodynamics and kinetics. A thorough understanding of thermodynamic principles will help to predict the stability of assembly while kinetic parameters facilitate the optimization of assembly and disassembly rates.