Self-assembling systems play a significant role in physiological functions and have therefore attracted tremendous attention due to their great potential for applications in energy, biomedicine and nanotechnology. Peptides, consisting of amino acids, are among the most popular building blocks and programmable molecular motifs. Nanostructures and materials assembled using peptides exhibit important potential for green-life new technology and biomedical applications mostly because of their bio-friendliness and reversibility. The formation of these ordered nanostructures pertains to the synergistic effect of various intermolecular non-covalent interactions, including hydrogen-bonding, π-π stacking, electrostatic, hydrophobic, and van der Waals interactions. Therefore, the self-assembly process is mainly driven by thermodynamics; however, kinetics is also a critical factor in structural modulation and function integration. In this review, we focus on the influence of thermodynamic and kinetic factors on structural assembly and regulation based on different types of peptide building blocks, including aromatic dipeptides, amphiphilic peptides, polypeptides, and amyloid-relevant peptides.

An injectable and self-healing collagen-gold hybrid hydrogel is spontaneously formed by electrostatic self-assembly and subsequent biomineralization. It is demonstrated that such collagen-based hydrogels may be used as an injectable material for local delivery of therapeutic agents, showing enhanced antitumor efficacy.

Peptide-tuned self-assembly of functional components offers a strategy towards improved properties and unique functions of materials, but the requirement of many different functions and a lack of understanding of complex structures present a high barrier for applications. Herein, we report a photosensitive drug delivery system for photodynamic therapy (PDT) by a simple dipeptide- or amphiphilic amino-acid-tuned self-assembly of photosensitizers (PSs). The assembled nanodrugs exhibit multiple favorable therapeutic features, including tunable size, high loading efficiency, and on-demand drug release responding to pH, surfactant, and enzyme stimuli, as well as preferable cellular uptake and biodistribution. These features result in greatly enhanced PDT efficacy in vitro and in vivo, leading to almost complete tumor eradication in mice receiving a single drug dose and a single exposure to light.

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Supramolecular photosensitizer nanodrugs that combine the flexibility of supramolecular self-assembly and the advantage of spatiotemporal, controlled drug delivery are promising for dedicated, precise, noninvasive tumor therapy. However, integrating robust blood circulation and targeted burst release in a single photosensitizer nanodrug platform that can simultaneously improve the therapeutic performance and reduce side effects is challenging. Herein, we demonstrate a multicomponent coordination self-assembly strategy that is versatile and potent for the development of photodynamic nanodrugs. Inspired by the multicomponent self-organization of polypeptides, pigments, and metal ions in metalloproteins, smart metallo-nanodrugs are constructed based on the combination and cooperation of multiple coordination, hydrophobic, and electrostatic noncovalent interactions among short peptides, photosensitizers, and metal ions. The resulting metallo-nanodrugs have uniform sizes, well-defined nanosphere structures, and high loading capacities. Most importantly, multicomponent assembled nanodrugs have robust colloidal stability and ultrasensitive responses to pH and redox stimuli. These properties prolong blood circulation, increase tumor accumulation, and enhance the photodynamic tumor therapeutic efficacy. This study offers a new strategy to harness robust, smart metallo-nanodrugs with integrated flexibility and multifunction to enhance tumor-specific delivery and therapeutic effects, highlighting opportunities to develop next-generation, smart photosensitizing nanomedicines.

The transition of peptides and proteins from the solution phase into fibrillar structures is a general phenomenon encountered in functional and aberrant biology and is increasingly exploited in soft materials science. However, the fundamental molecular events underpinning the early stages of their assembly and subsequent growth have remained challenging to elucidate. Here, we show that liquid–liquid phase separation into solute‐rich and solute‐poor phases is a fundamental step leading to the nucleation of supramolecular nanofibrils from molecular building blocks, including peptides and even amphiphilic amino acids. The solute‐rich liquid droplets act as nucleation sites, allowing the formation of thermodynamically favorable nanofibrils following Ostwald's step rule. The transition from solution to liquid droplets is entropy driven while the transition from liquid droplets to nanofibrils is mediated by enthalpic interactions and characterized by structural reorganization. These findings shed light on how the nucleation barrier toward the formation of solid phases can be lowered through a kinetic mechanism which proceeds through a metastable liquid phase.

The review introduces several methods for fabrication of robust peptide-based hydrogels and their biological applications in the fields of drug delivery and antitumor therapy, antimicrobial and wound healing materials, and 3D bioprinting and tissue engineering.

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