Pharmaceuticals often suffer from limitations such as low solubility, low stability, and  short half-life. To address these challenges and reduce the need for frequent drug administrations, a more efficient delivery is required. In this context, the development of controlled drug delivery systems, acting as a protective depot for the drug, has expanded significantly over the last decades. Among these, injectable hydrogels have emerged as a promising platform, especially in view of the rise of biologicals as therapeutics. Hydrogels are functional, solid-like biomaterials, composed of cross-linked hydrophilic polymers and high water content. Their physical properties, which closely mimic the extracellular matrix, make them suitable for various biomedical applications. This review discusses the different types of hydrogel systems and their self-assembly process, with an emphasis on peptide-based hydrogels. Due to their structural and functional diversity, biocompatibility, synthetic accessibility, and tunability, peptides are regarded as promising and versatile building blocks. A comprehensive overview of the variety of peptide hydrogels is outlined, with β-sheet forming sequences being highlighted. Key factors to consider when using peptide hydrogels as a controlled drug delivery system are reviewed, along with a discussion of the main drug release mechanisms and the emerging trend towards affinity-based systems to further refine drug release profiles.

The supramolecular self-assembly of peptides offers a promising avenue for both materials science and biological applications. Peptides have garnered significant attention in molecular self-assembly, forming diverse nanostructures with α-helix, β-sheet, and random coil conformations. These self-assembly processes are primarily driven by the amphiphilic nature of peptides and stabilized by non-covalent interactions, leading to complex nanoarchitectures responsive to environmental stimuli. While extensively studied in biomedical applications, including drug delivery and tissue engineering, their potential applications in the fields of piezoresponsive materials, conducting materials, catalysis and energy harvesting remain underexplored. This review comprehensively elucidates the diverse material characteristics and applications of self-assembled peptides. We discuss the multi-stimuli-responsiveness of peptide self-assemblies and their roles as energy harvesters, catalysts, liquid crystalline materials, glass materials and contributors to electrical conductivity. Additionally, we address the challenges and present future perspectives associated with peptide nanomaterials. This review aims to provide insights into the versatile applications of peptide self-assemblies while concisely summarizing their well-established biomedical roles that have previously been extensively reviewed by various research groups, including our group.

The demand for synthetic soft materials with bioinspired structures continues to grow. Material applications range from in vitro and in vivo tissue mimics to therapeutic delivery systems, where well-defined synthetic building blocks offer precise and reproducible property control. This work examines a synthetic assembling peptide, specifically a multifunctional collagen mimetic peptide (mfCMP) either alone or with reactive macromers, for the creation of responsive hydrogels that capture aspects of soft collagen-rich tissues. We first explored how buffer choice impacts mfCMP hierarchical assembly, in particular, peptide melting temperature, fibril morphology, and ability to form physical hydrogels. Assembly in physiologically relevant buffer resulted in collagen-like fibrillar structures and physically assembled hydrogels with shear-thinning (as indicated through strain-yielding) and self-healing properties. Further, we aimed to create fully synthetic, composite peptide-polymer hydrogels with dynamic responses to various stimuli, inspired by the extracellular matrix (ECM). Specifically, we established mfCMP-poly(ethylene glycol) (PEG) hydrogel compositions that demonstrate increasing non-linear viscoelasticity in response to applied strain as the amount of assembled mfCMP content increases. Furthermore, the thermal responsiveness of mfCMP physical crosslinks was harnessed to manipulate the composite hydrogel mechanical properties in response to changes in temperature. Finally, cells relevant in wound healing, human lung fibroblasts, were encapsulated within these peptide-polymer hydrogels to explore the impact of increased mfCMP, and the resulting changes in viscoelasticity, on cell response. This work establishes mfCMP building blocks as versatile tools for creating hybrid and adaptable systems with applications ranging from injectable shear-thinning materials to responsive interfaces and synthetic ECMs for tissue engineering.

Self-assembled hydrogels, fabricated through diverse non-covalent interactions, have been extensively studied in regenerative medicines. Inspired from bioactive functional motifs of ECM protein, short peptide sequences have shown remarkable abilities to replicate the intrinsic features of the natural extracellular milieu. In this direction, we have fabricated two short hydrophobic bioactive sequences derived from the laminin protein i. e., IKVAV and YIGSR. Based on the substantial hydrophobicity of these peptides, we selected a co-solvent approach as a suitable gelation technique that included different concentrations of DMSO as an organic phase along with an aqueous solution containing 0.1 % TFA. These hydrophobic laminin-based bioactive peptides with limited solubility in aqueous physiological environment showed significantly enhanced solubility with higher DMSO content in water. The enhanced solubility resulted in extensive intermolecular interactions that led to the formation of hydrogels with a higher-order entangled network along with improved mechanical properties. Interestingly, by simply modulating DMSO content, highly tunable gels were accessed in the same gelator domain that displayed differential physicochemical properties. Further, the cellular studies substantiated the potential of these laminin-derived hydrogels in enhancing cell-matrix interactions, thereby reinforcing their applications in tissue engineering.

Diabetes is a widespread epidemic that includes a number of comorbid conditions that greatly increase the chance of acquiring other chronic illnesses. Every year, there are significantly more people with diabetes because of the rise in type-2 diabetes prevalence. The primary causes of illness and mortality worldwide are, among these, hyperglycemia and its comorbidities. There has been a lot of interest in the creation of peptide-based hydrogels as a potentially effective platform for the treatment of diabetes and its consequences. Here, we emphasize the use of self-assembled hydrogel formulations and their unique potential for the treatment/management of type-2 diabetes and its consequences. (i.e., wounds). Key aspects covered include the characteristics of self-assembled peptide hydrogels, methods for their preparation, and their pre-clinical and clinical applications in addressing metabolic disorders such as type-2 diabetes.

Effective drug delivery is essential for cancer treatment. Drug delivery systems, which can be tailored to targeted transport and integrated tumor therapy, are vital in improving the efficiency of cancer treatment. Peptides play a significant role in various biological and physiological functions and offer high design flexibility, excellent biocompatibility, adjustable morphology, and biodegradability, making them promising candidates for drug delivery. This paper reviews peptide-mediated drug delivery systems, focusing on self-assembled peptides and peptide-drug conjugates. It discusses the mechanisms and structural control of self-assembled peptides, the varieties and roles of peptide-drug conjugates, and strategies to augment peptide stability. The review concludes by addressing challenges and future directions.

With the ongoing development of peptide self-assembling materials, there is growing interest in exploring novel functional peptide sequences. From short peptides to long polypeptides, as the functionality increases, the sequence space is also expanding exponentially. Consequently, attempting to explore all functional sequences comprehensively through experience and experiments alone has become impractical. By utilizing computational methods, especially artificial intelligence enhanced molecular dynamics (MD) simulation and de novo peptide design, there has been a significant expansion in the exploration of sequence space. Through these methods, a variety of supramolecular functional materials, including fibers, two-dimensional arrays, nanocages, etc., have been designed by meticulously controlling the inter- and intramolecular interactions. In this review, we first provide a brief overview of the current main computational methods and then focus on the computational design methods for various self-assembled peptide materials. Additionally, we introduce some representative protein self-assemblies to offer guidance for the design of self-assembling peptides.

The unique optical and electronic properties of living systems are impressive. Peptide-based supramolecular self-assembly systems attempt to mimic these properties by preparation optical/electronic function materials with specific structure through simple building blocks, rational molecular design, and specific kinetic stimulation. From the perspective of building blocks and assembly strategies, the unique optical and electronic properties of peptide-based nanostructures, including peptides self-assembly and peptides regulate the assembly of external function subunits, are systematically reviewed. Additionally, their applications in biomedicine, sensing, and energy storage are also highlighted. This bioinspired peptide-based function material is one of the hot candidates for the new generation of green intellect materials, with many advantages such as biocompatibility, environmental friendliness, and adjustable morphology.

Self-assembling peptides (SAPs) have been increasingly studied as hydrogel-former gelators because they can create biocompatible environments. A common strategy to trigger gelation, is to use a pH variation, but most methods result in a change in pH that is too rapid, leading to gels with hardly reproducible properties. Here, we use the urea-urease reaction to tune gel properties, by a slow and uniform pH increase. We were able to produce very homogeneous and transparent gels at several SAP concentrations, ranging from c=1g/L to c=10g/L. In addition, by exploiting such a pH control strategy, and combining photon correlation imaging with dynamic light scattering measurements, we managed to unravel the mechanism by which gelation occurs in solutions of (LDLK)3-based SAPs. We found that, in diluted and concentrated solutions, gelation follows different pathways. This leads to gels with different microscopic dynamics and capability of trapping nanoparticles. At high concentrations, a strong gel is formed, made of relatively thick and rigid branches that firmly entrap nanoparticles. By contrast, the gel formed in dilute conditions is weaker, characterized by entanglements and crosslinks of very thin and flexible filaments. The gel is still able to entrap nanoparticles, but their motion is not completely arrested. These different gel morphologies can potentially be exploited for controlled multiple drug release.

Self-assembling peptides are a type of biomaterial rapidly emerging in the fields of biomedicine and material sciences due to their promise in biocompatibility and effectiveness at controlled release. These self-assembling peptides can form diverse nanostructures in response to molecular interactions, making them versatile materials. Once assembled, the peptides can mimic biological functions and provide a combinatorial delivery of therapeutics such as cytokines and drugs. These self-assembling peptides are showing success in biomedical settings yet face unique challenges that must be addressed to be widely applied in the clinic. Herein, we describe self-assembling peptides' characteristics and current applications in immunomodulatory therapeutics.