Supramolecular crafting of peptides as novel antimicrobial materials

Abstract

Antimicrobial peptides (AMPs) have attracted great attention over the past few years as promising candidates to combat bacterial resistance. However, their small molecule nature poses limitations in stability, toxicity, and pharmacokinetics, restricting their in vivo and clinical uses. Supramolecular assembly of AMPs into well-defined nanostructures displays great potential to address the faced challenges, exhibiting unprecedented advantages over the unimolecular ones. The nanostructured AMPs could amplify therapeutic outcomes through enhanced germicidal capacity, improved serum stability, increased host compatibility and prolonged circulation. More importantly, through rational design, one can effectively modulate the interactions between peptides and microbes, promoting capabilities for bacterial capturing, and membrane targeting and disruption. In this review, the recent progress of supramolecular peptide assemblies as antimicrobial materials will be discussed with a focus on the design principle, self-assembly behavior, and applications of supramolecular AMPs. This supramolecular platform could provide excellent alternatives towards traditional antibiotics and AMPs, offering new solutions to tackle drug-resistant infectious pathogens.

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Wider impact

This review highlights recent advancements in peptide-based antimicrobial nanomaterials, focusing on molecular design, self-assembly behavior, and their resulting antibacterial applications and superiorities. Bacterial combatting has attracted significant interest in the areas of healthcare, drug development, bioengineering and materials science. Supramolecular assembly of antimicrobial peptides (AMPs) brings unprecedented advantages over the unimolecular AMPs as promising candidates to address bacterial resistance. Future efforts should focus on comprehensively elaborating the correlation between molecular design, supramolecular assembly and antimicrobial efficacy with the help of artificial intelligence (AI). In addition, supramolecular AMPs with enhanced selectivity, smart responsiveness, controlled disassembly and degradation, and mass production are desired. We believe that this review will be appealing to researchers in the field of AMPs, supramolecular materials and self-assembly, inspiring the integration of multidisciplinary approaches in materials science and engineering.

1. Introduction

Pathogens are closely associated with various diseases (e.g., skin abscesses, necrotizing pneumonia, and sepsis), significantly threatening human life and health.^1–3 Following the discovery of penicillin, a rich collection of traditional antibiotics, such as cephalexin, erythromycin, ciprofloxacin, gentamycin, and vancomycin, have been developed to combat bacterial infections.^4–6 These antibiotics generally associate with bacteria through cytomembrane targets and interfere with bacterial biochemical processes (e.g., structure, function, multiplication and metabolism), ultimately exerting inhibitory effects.⁷ However, due to antibiotic abuse, the bacteria may undergo mutations that can alter the specific targets for traditional antibiotics, upregulate efflux pumps to expel small-molecule drugs, and produce drug-degrading enzymes, which contribute to the emergence of multidrug resistance (MDR).^8–10 A recent report predicts that by 2050, drug-resistant bacterial infections could cause more than 10 million deaths worldwide, surpassing the number of deaths caused by cancer.¹¹ Nowadays, several novel antibiotics have been developed that specifically target the mechanism of resistance.^12,13 However, the development of these new antibiotics is hindered by long research and development cycles and high costs, making it difficult to keep pace with the growing threat of antibiotic-resistant pathogens. Thus, there is an urgent need to develop new drugs with mechanisms distinct from traditional antibiotics.

Antimicrobial peptides (AMPs) are an emerging class of antibacterial drugs with excellent biocompatibility and broad-spectrum bactericidal activity.¹⁴ Several natural AMPs, such as LL-37, human α-defensin 6 (HD6), and cecropins, have been found in human and animal bodies.^15–17 AMPs normally possess positive charges and show varied action mechanisms compared with traditional antibiotics. In one aspect, they can adhere to the bacterial membrane surface via electrostatic interactions, and subsequently induce leakage of intracellular substances.^18,19 In the other aspect, they can effectively traverse bacterial cell membranes and bind to intracellular targets. The unique membrane-disruptive mechanism endows AMPs with more effectiveness in the treatment of bacterial resistance infections. Moreover, AMPs can also play a crucial role in modulating the innate immune system, including promoting wound healing, stimulating anti-inflammatory factors, and enhancing phagocytosis.²⁰ These incomparable features make AMPs a promising platform for combating antibiotic resistance. Numerous efforts have been devoted to optimizing their molecular design to screen the most potent candidates in vitro; however, several intrinsic limitations still exist when trying to extrapolate the findings to in vivo settings and the clinic. The physical and chemical stability of AMPs will be significantly compromised upon entering the organism due to the presence of salts and proteases in body fluids. Also, small molecule AMPs are swiftly eliminated by the kidneys, leading to a shortened circulation time in the body. In addition, certain side effects, including protein corona formation and hemolytic toxicity, have been observed in the use of AMPs.²¹

Supramolecular assembly has been recognized as one of the most effective strategies to significantly enhance the physiochemical and pharmacological properties of peptide-based materials.^22–24 Utilizing non-covalent interactions, including hydrogen bonding, π–π stacking, and electrostatic interactions, peptides can self-assemble into discrete, well-defined nanostructures. Upon assembly, as compared with unimolecular peptides, the highly ordered supramolecular nanostructures can shield the peptides from proteolytic degradation and prolong the circulation time, thereby improving stability and bioavailability.²⁵ Additionally, peptide assemblies can undergo reversible changes, dynamically respond to environmental stimuli, and exhibit tunable structure–function relationships.²⁶ Therefore, the proper integration of supramolecular design with AMPs displays great capacities to address the faced challenges, empowering the development of peptide-based antimicrobial nanomaterials.^27,28 To create potential alternatives, the physicochemical properties (e.g., size, shape, surface chemistry) of supramolecular peptide-based antimicrobials should be carefully regulated. For example, the size of nanostructures critically influences their biodistribution and clearance in vivo. Peptide assemblies with optimized dimensions effectively evade rapid clearance by both the renal and mononuclear phagocyte systems, thereby enhancing penetration and localization to infection sites.²⁹ The assembled morphology is another important parameter of peptide-based supramolecular antimicrobials. The morphological transformation induced variations in hydrodynamic behavior, receptor recognition, and internalization pathways among nanostructures can markedly impact their antimicrobial activities.²⁵ Furthermore, the surface properties of supramolecular AMPs can modulate interactions with cell membranes and bacterial cell walls while influencing protein corona formation. Appropriate surface modifications reduce toxicity and nonspecific adsorption, thereby enhancing biocompatibility and stability.³⁰ In addition, self-assembled peptide nanofibers can entangle in the physiological environment to form supramolecular hydrogels with antimicrobial properties. The porous structure and dynamic properties of peptide hydrogels enable effective encapsulation and controlled release of antimicrobial agents, ensuring sustained antibacterial activity at the infection site. At the same time, these peptide networks can mimic the action mechanism of natural AMPs, such as HD6, by capturing bacteria at pathological sites and preventing their invasion of host cells.^31–33 Some excellent reviews have been summarized, focusing on the topology, assembled morphology and therapeutic efficacy of AMPs.^34–37

In this review, we aim to summarize the molecular design, self-assembly behavior and applications of antibacterial peptide nanostructures (Fig. 1). Specifically, we first introduce the primary and secondary structures, physicochemical properties, and antibacterial mechanisms of small molecule AMPs. In the later section, we classify the examples of supramolecular AMPs and elaborate on the design principles that govern the secondary structure and assembly behavior of diverse peptide building blocks. Subsequently, we highlight the applications and advantages of peptide assemblies in the field of bacterial combating. Finally, we briefly discuss the challenges and potential directions of peptide-based supramolecular antimicrobial materials. With the purpose of addressing the threat of MDR, we hope that our review underscores the exceptional antibacterial properties of peptide-based materials crafted by supramolecular strategies that could potentially serve as supplements and alternatives to traditional antibiotics.

Fig. 1 Molecular design and applications of supramolecular AMPs.

2. Small molecule antimicrobial peptides (AMPs)

The chemical features of the peptide backbone and side groups endow AMPs with diverse sequences, compositions and conformations, which may significantly influence their physicochemical properties, antibacterial mechanisms and the corresponding efficacy. As a result, continuous optimization of molecular design could bring more insightful inspirations in exploiting novel AMPs and discovering principles of action mechanisms. In this section, we will give a brief overview of the primary and secondary structures of AMPs and discuss their main antimicrobial mechanisms, underscoring their great potential in antimicrobial therapy. More comprehensive information about small molecule AMPs has been summarized in some other excellent reviews.^38–40

2.1. Structures of AMPs

The primary structures of AMPs generally refer to the peptide sequence, chirality of amino acid residues, and topology. By rationally designing the peptide sequences, the spatial arrangement of charge and hydrophobicity in AMPs could be precisely manipulated. Most of the AMPs contain amino acid residues with positive charge, leading to selective binding with the negatively charged bacterial membranes. With the gradual increase of positive charge, the antibacterial efficacy of AMPs can be significantly enhanced. However, once the threshold is exceeded, the excessive positive charge may also result in toxicity toward normal cells. Moreover, the hydrophobicity of AMPs also exerts a paramount influence on determining the permeability process of AMPs through the hydrophobic regions of the bacterial membrane.^41,42 Therefore, it is of great significance to precisely modulate the levels of positive charge and hydrophobicity to achieve the optimal balance between antibacterial activity and low toxicity. Additionally, the chirality of amino acids can influence the biological stability of AMPs, and the substitution of D-amino acids for L-amino acids can contribute to the evasion of protease recognition.⁴³ Beyond typical linear AMPs, the incorporation of topological structures has broadened the scope of peptide-based antimicrobial agents, encompassing polypeptides, cyclic peptides, and dendritic peptides.^44–47

Besides the primary structure, AMPs also exhibit a diverse range of secondary structures, which are key factors in modulating their interactions with bacteria. The conformational flexibility inherent to these secondary structures enables AMPs to adopt specific shapes that are essential for effective binding to bacterial membranes. Based on the distinct characteristics of these secondary structures, AMPs can be categorized into several subclasses, including α-helix, β-sheet, α/β mixed, and random-coil structures. The α-helical AMPs (e.g., magainin-II and LL-37, derived from the skin of Xenopus laevis and human neutrophils) primarily exist as random coil structures in aqueous solution and transform into an amphipathic helical structure upon parallelly contacting with hydrophobic membranes.⁴⁸ The β-sheet conformation of AMPs typically comprises at least one pair of double β-strands, and these peptides often contain cysteine residues that can form one or more intramolecular disulfide bonds. The disulfide bonds can fix the structure and biological functionality of β-sheet AMPs, thereby impeding significant alterations in their structures within a membrane environment.⁴⁹ Representative examples of AMPs with β-sheet structures include human α-defensin 5 (HD5) and lactoferricin B, which are derived from the human small intestine and bovine lactoferrin, respectively. AMPs can also possess mixed α-helical and β-sheet structures, resulting in greater diversity and complexity compared to those with a single structure.

2.2. Mechanisms of AMPs

Unlike traditional antibiotics, AMPs can exert therapeutic effects via direct or indirect mechanisms. In the direct mechanism, AMPs disrupt the bacterial membrane, leading to bacterial inhibition or killing.⁵⁰ In the indirect mechanism, they modulate the host immune response, so as to enhance the body's defense against infections.^38,51 Such unique characteristics enable AMPs to serve as a critical defense against bacterial infections, exhibiting a low susceptibility to resistance.

After selectively binding with bacterial membranes through electrostatic interactions, the membrane may be disrupted directly through multiple models (i.e., barrel-stave model, carpet model, toroidal-pore model). Bacterial membranes often contain negatively charged phospholipids, while the mammalian membranes are predominantly composed of zwitterionic phospholipids, and their outer leaflets are electrically neutral under physiological pH conditions.^52,53 The distinct membrane compositions of mammalian and bacterial cells are a critical determinant of AMPs’ selectivity and activity. Meanwhile, AMPs may also alter the permeability of negatively charged cytoplasmic membranes, facilitating subsequent penetration of the hydrophobic domain into the cell membrane.^50,54 Once internalized, AMPs can impede DNA transcription and replication, RNA synthesis, protein synthesis and folding, as well as enzyme activity, while also interfering with cell wall synthesis, ultimately achieving bactericidal effects.^55,56

Besides the direct antimicrobial activity, AMPs are essential for regulating immune responses, and enhancing both innate and adaptive immunity, making them promising candidates as therapeutics for infections and immune-related disorders.⁵⁷ They activate the innate immune system by stimulating immune cells such as macrophages and neutrophils, which in turn release pro-inflammatory cytokines and recruit additional immune cells to the site of infection.⁵⁸ Additionally, the function of antigen-presenting cells can also be enhanced, further promoting the activation of adaptive immunity by facilitating T cell responses. Beyond their pro-inflammatory effects, some AMPs also possess anti-inflammatory properties that help to regulate excessive immune activation and prevent tissue damage. Furthermore, certain AMPs contribute to tissue repair and wound healing by promoting cell migration, angiogenesis, and collagen formation, while also potentially supporting immune memory.

3. Supramolecular design of peptide-based antimicrobials

Despite the considerable therapeutic potential of AMPs, certain challenges, including instability in the physiological environment, low bioavailability and potential toxic side effects, persist in translating peptide-based antimicrobials into clinical practice. Supramolecular assembly of peptides can significantly enhance their bioavailability, which exhibits great potential to address the challenges faced by small-molecule AMPs. The aggregation of AMPs into well-defined nanostructures could alter the physicochemical and pharmacological properties of the individual peptides. For peptide assemblies, non-covalent intermolecular interactions and secondary structures are very important in determining the self-assembly behavior.^59,60 Multiple non-covalent interactions, including hydrophobic, hydrogen bonding, aromatic and electrostatic interactions, cooperatively drive the assembly of peptide monomers into higher-order nanostructures mainly including nanoparticles, nanovesicles, nanofibers, and nanobelts (Fig. 2). Therefore, understanding how molecular design dictates the primary and secondary structures of AMPs, and regulates and balances multiple interactions is essential to construct supramolecular antimicrobial materials. Indeed, in the specific design of an AMP, the choice of structure-promoting amino acids and conjugation of hydrophobic groups are integral for the formation of their secondary structures and the resulting supramolecular nanostructures. In this section, we will summarize the molecular design strategies underlying supramolecular peptide nanostructures with a particular focus on tuning the hydrophilic–hydrophobic proportion of amino acids, incorporating external functional groups, and introducing multiple components in the system. More specifically, we have classified them into several representative categories, including amphiphilic peptides, lipidic peptides, aromatic peptides, cholesteric peptides, polypeptides and co-assembling peptides.

Fig. 2 Supramolecular antimicrobial peptide design and self-assembly into functional nanostructures mediated by non-covalent interactions.

3.1. Amphiphilic peptides

Amphiphilic peptides, consisting of both charged and hydrophobic amino acids, serve as a typical type of self-assembling peptides.⁶¹ The charged, normally cationic, peptides enable interaction with the negatively charged bacterial membrane and increase the water solubility to promote self-assembly. More importantly, the hydrophobic segments may significantly enhance the hydrophobicity and aromaticity of AMPs and promote their aggregation in aqueous solutions. With the synergism of multiple interactions, these amphiphilic peptides can self-assemble into diverse well-defined nanostructures. In addition, the hydrophobic peptide segments facilitate lipid bilayer penetration, inducing structural disorder and potent antimicrobial activity.

For instance, Chen et al. synthesized a series of Ac-A_mK-NH₂ analogues with varying tail lengths (m = 3, 6, and 9) and investigated the effect of hydrophobic tail length on the assembled morphology and antibacterial performance of these amphiphilic peptides (Fig. 3a).⁶² They observed entropy-mediated core formation driven by the hydrophobic clustering of alanine residues. With the increase of tail length, the molecular packing transferred from loosely aggregated assemblies to compact nanorods with β-sheet stacking (notably for m = 9). This structural transformation also enhanced membrane penetration, thereby improving antibacterial efficacy compared with the shorter analogue A₃K-NH₂. Furthermore, they monitored the aggregated state of peptides on the surface of Escherichia coli (E. coli) by high-resolution atomic force microscopy (AFM). The results showed that both peptide monomers and their self-assembled nanostructures bind directly to the bacterial envelope and subsequently induce membrane disruption by a detergent-like mechanism.⁶³ By employing a similar amphiphilic design, Bai and his colleagues developed a self-assembling peptide Ac-VVVVVVKKK-NH₂, which can spontaneously self-assemble into spherical nanoparticles through dominant hydrophobic interactions between valine residues.⁶⁴ When the peptides were exposed to fetal bovine serum or plasma amine oxidase, the ε-amino groups of lysine could be enzymatically modified, altering the amphiphilic balance and subsequently triggering a morphological transition to nanofibers. The resultant nanofibers possessed a reduced surface charge density and enhanced hydrophobic exposure, significantly amplifying membrane-disruptive capabilities.

Fig. 3 Supramolecular AMP design of amphiphilic peptides. (a) A9K peptides self-assembled into nanorods and their mechanism of action leading to bacterial membrane penetration and destruction. Reproduced with permission.⁶² Copyright 2010 American Chemical Society. (b) Self-assembling peptide anchored at the mycolipid–water interface, with the secondary structure changing in response to pH. Reproduced with permission.⁶⁵ Copyright 2021 Springer Nature. (c) Chemical structure of terminal functional groups of FF, which can self-assemble into nanotube structures in response to stimuli. Reproduced with permission.⁶⁶ Copyright 2018 Elsevier. (d) The molecular structure of self-assembling peptides showing the sequential position of DOPA. Peptides assemble into fibrillar networks through interactions of side chain residues. Reproduced with permission.⁶⁷ Copyright 2021 Wiley.

Tryptophan (W) is usually introduced to AMPs to promote their self-assembly capabilities.⁶⁸ Due to its unique indole ring structure, the W residue prefers to be located at the lipid bilayer interface and helps stabilize the interactions between the peptide and the cell membrane.^69,70 This structural motif can also serve as an effective assembly promoter by stabilizing peptide structures through aromatic associations, facilitating the folding of peptides into the β-hairpin conformation and the subsequent formation of nanostructures.^71,72 For example, Simonson and co-workers de novo designed a W-rich helical peptide (KRWHWWRRHWVVW-NH₂) with a sophisticated, pH-dependent self-assembly process that mimics key features of the mycobacterial porin MspA (Fig. 3b).⁶⁵ At physiological pH, the helical peptide predominantly adopts a mixed α-helical and β-sheet conformation and forms laminated proto-fibrillar assemblies driven by intermolecular tryptophan pairing. In this state, the peptide aggregates into stable nanostructures through a combination of hydrogen bonding, π–π stacking between W residues, and hydrophobic interactions. Under acidic conditions, protonation of histidine residues induces intramolecular electrostatic repulsion, which increases the peptide's conformational flexibility. This increment in flexibility facilitates the formation of a tryptophan zipper motif that resembles β-sheet-rich structures, leading to the assembly of monomorphic amyloid-like fibers and selectively killing pathogens. In addition to positively charged amino acid residues, further introduction of anionic residues may also create supramolecular assemblies via a synergy of electrostatic interactions and tryptophan associations between peptides. The Shan group designed a dimeric AMP (2D2W), in which WWCRR-AAA-RRRR-NH₂ and DDCWW are linked by disulfide bonds.⁷³ The electrostatic interactions enable the attractions among oppositely charged peptide molecules; meanwhile, the aromatic stacking between W residues induces the regular arrangement of peptides and directs the formation of fibrous nanostructures.

Phenylalanine (F) is another residue often used in the supramolecular design of amphiphilic peptides. For instance, diphenylalanine (FF), as a key recognition motif of β-amyloid proteins, not only presents exceptional self-assembly capability, but also exhibits antibacterial activity.^74,75 In one study, the terminal functional groups of FF and its enantiomer ff were modified to amino (-NH₂) and carboxylic acid (-COOH).⁶⁶ All these peptides (NH₂-FF-COOH, NH₂-FF-COOH and NH₂-FF-NH₂) can self-assemble into well-defined tubular structures with long persistence lengths in solution (Fig. 3c). The self-assembly is driven by intermolecular π–π interactions between adjacent phenyl groups, hydrophobic interactions, and hydrogen bonds in the surrounding solvent, resulting in a predominantly β-sheet secondary structure. Moreover, the additional terminal amine increases the cationicity of the peptides, thereby altering the antibacterial selectivity and mammalian cytotoxicity profiles of these peptide nanotubes. Such FF motif design was further extended to create supramolecular peptide hydrogels by incorporating additional residues. In particular, the minimal amphiphilic β-pleated motif, represented by the sequence F–X–F (where X denotes a hydrophilic amino acid), can provide π–π interactions between phenylalanine side chains, which interact across antiparallel neighboring β-strands, enabling the formation of fibril assemblies.⁷⁶ Specifically, FKF forms pH-responsive supramolecular nanostructures that entangle into hydrogels under weakly acidic conditions.⁷⁷ The pH-dependent self-assembly produces distinct phases, including slender needle-like structures, uniform fibers, sheets, and tubular structures. Notably, FKF exhibits significant antibacterial activity once organized into a fibrous network, whereas its activity in the solution state is nearly negligible.

Besides the cases mentioned above, β-hairpin peptides also appear in the design of supramolecular peptide antimicrobials. For example, Schneider et al. designed a symmetric β-hairpin peptide, PEP8R (VKVRVRVRV^DPPTRVRVRVKV), featuring two β-strands composed of alternating valine and arginine residues, connected by a β-turn sequence (V^DPPT).⁷⁸ In an aqueous solution, the peptide maintains a random coil conformation, due to the charge repulsion by protonated guanidyl groups. However, upon charge screening by NaCl buffer, the peptide folds into an amphiphilic β-hairpin structure, which rapidly self-assembles into β-sheet-rich filaments and ultimately intertwines to form a 3D network. Inspired by mussel adhesive proteins, they further introduced 3,4-dihydroxy-L-phenylalanine (DOPA, named Ÿ) into the system and screened the DOPA's sequential position. They developed three AMPs, M1DOPA1 (VKVKVKVKV^DPPTKVŸVKVKV-NH₂), M1DOPA2 (VKVKVKVKV^DPPTKVKVKVŸV-NH₂), and MIKA2 (VKVKVRVKV^DPPTKVKVRVŸV-NH₂).⁶⁷ Similar to PEP8R, these peptides self-assembled into fibers in buffer with an accelerated assembly process upon heating (Fig. 3d). The β-sheet-rich fiber network can form antimicrobial coating that shows significant inhibitory effects against methicillin-resistant Staphylococcus aureus (MRSA) and Staphylococcus epidermidis.

3.2. Lipidic peptides

Lipidic peptides have emerged as an important class of AMPs, some of which are already on the market or in clinical stages, such as daptomycin, polymyxin, etc.^79,80 The molecular structure of these lipidic AMPs coincides with the design of classic peptide amphiphiles (PAs), where the fatty acid chains are covalently conjugated to the termini of peptide segments. On the one hand, lipidation can modulate their hydrophobicity and facilitate the formation of nanostructures.⁸¹ On the other hand, lipidation can also enhance the interaction between peptides and cellular membranes, thus augmenting their antimicrobial capacities.^82,83 Moreover, the nanosized feature and the reversible and high-affinity binding between the alkyl chains and albumin can optimize the pharmacokinetics of peptide drugs.^84–86

In the design and biological evaluation of lipidic peptides, the effect of alkyl tails on self-assembly behavior as well as the resultant antimicrobial capacity has been investigated. For instance, three lipidic AMPs G(IIKK)₃I-NH₂ (G3), C₈-G(IIKK)₂I-NH₂ (C8G2), and C₁₂-G(IIKK)₂I-NH₂ (C12G2) were developed (Fig. 4a).⁸⁷ Transmission electron microscopy (TEM) revealed that G3 formed droplet-like nanostructures, whereas both C8G2 and C12G2 formed nanofibers with critical aggregation concentrations (CACs) of 50 μg mL⁻¹ and 3 μg mL⁻¹, respectively. Importantly, the C12G2 peptide formed stable nanofiber hydrogels with shear-thinning and reversible properties. The injectable peptide hydrogel demonstrated antibacterial efficacy comparable to that of vancomycin in eradicating MRSA infections. This hydrogel was further developed as an oral preparation, exhibiting rapid membrane dissolution and enhanced killing of Helicobacter pylori compared to the antibiotic controls (omeprazole, amoxicillin, clarithromycin, OAC).⁸⁸ In another comparable example, Nandi and his colleagues modified the peptide's N-terminus with alkyl chains of varied length, which regulated self-assembly behavior and hydrogel formation.⁸⁹ Specifically, they synthesized five peptides (P1–P5) with the general chemical formula H₂N-(CH₂)_nCONH-Phe-CONHC₁₂ (n = 1–5). All five peptides formed self-supporting hydrogels in aqueous solution (Fig. 4b). Scanning electron microscopy (SEM) examination revealed that all dried hydrogel samples were formed by entangled fibrous structures. However, P3, P4, and P5 displayed markedly different morphologies from those of P1 and P2. The gelators with longer alkyl chains (P3–P5) formed ordered arrays of nanospheres that fused into nanofibers. They also found a decrease in minimum gelation concentration and an increase in thermal stability as the alkyl chain length of the gelator increased. These findings suggest that the greater number of –CH₂ units in P5 provides more van der Waals interaction sites than in the other gelators (P1–P4), allowing P5 molecules to pack more effectively in the gel state. In addition, the thermoresponsive hydrogel with a nanofiber network demonstrated broad-spectrum antibacterial activity in vitro and showed resistance to proteolytic degradation upon assembly.

Fig. 4 Supramolecular AMP design of lipidic peptides. (a) Self-assembly characterization of lipidic peptides. Reproduced with permission.⁸⁷ Copyright 2023 Wiley. (b) General molecular structure and hydrogelation of lipidic peptides. Reproduced with permission.⁸⁹ Copyright 2017 American Chemical Society. (c) Alkyl chains of varying lengths were conjugated to RV-18, resulting in nanoparticle formation and altered antibacterial activities. Reproduced with permission.⁹⁰ Copyright 2025 American Chemical Society. (d) Variations in chirality and sequence tuned the self-assembly behavior. Reproduced with permission.⁹¹ Copyright 2022 Elsevier.

Besides the influence of the length of fatty acid chains, the conjugation position at the C- or N-terminus of the peptides also can influence the self-assembly and antibacterial activity of lipidic peptides. For example, Zhang and co-workers conjugated fatty acids of varying chain lengths to the N- and C-termini of AMP RV-18 (RWRRFWGKAKRGIKKHGV), respectively (Fig. 4c).⁹⁰ Although all lipidic peptides could form nanoparticles, lauric acid acylation at the N-terminus was the optimal modification. Through precise modulation and screening of these chains, supramolecular AMPs with outstanding stability, selectivity and potency can be obtained. In addition, the chirality of encoded amino acids in the lipidic peptides also affects supramolecular assembly and antibacterial properties. Xie et al. designed three lipidic peptides, including two homochiral (C₁₆-V₄R₄ and C₁₆-V₄R₄, labeled as DD and LL, respectively) and one heterochiral (C₁₆-V₄R₄, labeled as DL) AMPs (Fig. 4d).⁹¹ All these peptides self-assembled in aqueous solution into helical nanofibers driven by hydrophobic interactions and intermolecular hydrogen bonding. The alternating chirality in the heterochiral peptide induces structural twisting between its two motifs and introduces internal strain that counteracts the inherent twist of β-sheets, resulting in a flatter right-handed helical structure, whereas the homochiral LL and DD peptides form left-handed and right-handed nanofibers, respectively. The DL peptide also shows a lower CAC than the LL and DD peptides, indicating a stronger self-assembly propensity and enhanced structural stability. Overall, chirality modulates the molecular arrangement of valine residues, directly influencing the supramolecular chirality and stability of the resulting nanofibers. Compared with the two homochiral AMPs, the heterochiral DL exhibits an enhanced aggregation capability, leading to superior bactericidal activity.

3.3. Aromatic peptides

Aromatic peptides are also utilized to create supramolecular antimicrobial materials. In the molecular design, the aromatic groups are conjugated at the N-terminus of the peptide sequences, which can not only enhance the hydrophobicity of peptide sequences, but also serve as the structural motif through the stacking of aromatic rings to direct the self-assembly process.⁹² The hydrophobic and π–π interactions from aromatic groups and hydrogen bonding in the peptide sequences act synergistically to contribute to the molecular packing, and regulate the morphology and function of supramolecular assemblies. Here, two main types of aromatic groups, 9-fluorenylmethoxycarbonyl (Fmoc) and small aromatic molecules (e.g., naphthyl group and pyrenyl group), are often used in the supramolecular assembly of AMPs and are summarized below.

The Fmoc group, known as the primary amine-protecting group in peptide synthesis, can serve as the aromatic motif in self-assembling peptides.⁹³ A variety of Fmoc-protected amino acids (e.g., Fmoc-F, Fmoc-W, Fmoc-M, Fmoc-Y) have been identified to successfully form fibrillar nanostructures and exhibit considerable antibacterial potential.^94,95 Furthermore, the strong aromatic interaction of the Fmoc residue is sufficient  to induce the self-assembly of longer peptide sequences. For example, Fmoc-peptides, such as Fmoc-FF, Fmoc-FFKK, Fmoc-FFFKK, and Fmoc-FFOO (O refers to ornithine), can all self-assemble into supramolecular nanofibers via π–π interactions and hydrogen bonding, and further entangle into supramolecular hydrogels with potent antibacterial activity against both Gram-positive and Gram-negative bacteria.^96,97 In another study, Fmoc-FFKK and silk fibroin were found to undergo orthogonal self-assembly to yield hybrid gels featuring heterogeneous double networks.⁹⁸ Subsequently, the Yan group fabricated an injectable dipeptide-fullerene supramolecular hydrogel, through hydrogen bonding and π–π interactions between Fmoc-FF and C₆₀-PTC.⁹⁹ The aggregation of fullerenes within the hydrogels was significantly inhibited by the non-covalent interaction between the peptides and fullerenes. To improve proteolytic resistance, L-FF was replaced with D-FF, leading to the design of Fmoc-D-Phe-D-Phe (ff), Fmoc-L-His-D-Phe-D-Phe (Hff), and Fmoc-L-Arg-D-Phe-D-Phe (Rff). The ff and Rff peptides can self-assemble into thread-like nanofibers, whereas the Hff peptide forms thin and long wavy nanofibers. Among them, the RFF gel shows great potential in the treatment of infections caused by antibiotic-resistant bacteria.¹⁰⁰ Later, the approach was extended to incorporate more non-natural aromatic amino acids into short AMPs. For example, peptides were synthesized with sequences such as Fmoc-D-Lys-Lys-1-Nal-1-Nal-Lys-NH₂, Fmoc-Dab-Dab-1-Nal-1-Nal-Dab-NH₂ and Fmoc-D-Dab-Dab-1-Nal-NH₂ (where Nal denotes dinaphthylalanine and Dab denotes 2,4-diaminobutyric acid).¹⁰¹ These peptides adopt extended β-sheet conformations, but they exhibit differences in their intermolecular π–π interactions and hydrogen bonding. As a result, Fmoc-D-Lys-Lys-1-Nal-1-Nal-Lys-NH₂ formed tightly twisted nanofibrils, Fmoc-Dab-Dab-1-Nal-1-Nal-Dab-NH₂ assembled into flat nanostructures, and Fmoc-D-Dab-Dab-1-Nal-NH₂ yielded densely bundled nanofibril networks. Ultimately, these peptides can self-assemble into filamentous nanostructures and trigger the formation of varied supramolecular hydrogels. More recently, Chakraborty et al. designed a di-Fmoc peptide Fmoc-K(Fmoc)-RGD, where the two Fmoc groups provided a sufficient π–π stacking effect and the RGD tripeptide is conducive to cell attachment. This peptide can also self-assemble into nanofibers and form antimicrobial hydrogels (Fig. 5a).¹⁰²

Fig. 5 Supramolecular AMP design of aromatic peptides. (a) Chemical structure of the di-Fomc peptide which can form a self-healing hydrogel. Reproduced with permission.¹⁰² Copyright 2021 Wiley. (b) Chemical structure and TEM images of naphthalene-based peptides. Reproduced with permission.¹⁰³ Copyright 2014 American Chemical Society. (c) Nap-FYp-Ada exerted antibacterial effects by forming nanofibers via in situ enzymatic self-assembly. Reproduced with permission.¹⁰⁴ Copyright 2023 Wiley.

Naphthalene (Nap) is another aromatic motif used to explore supramolecular materials with diverse structures and biological applications.^105,106 Similar to the Fmoc group, it is also frequently conjugated with FF to promote the formation of nanomaterials through synergistic π–π stacking and hydrophobic interactions. In one example, the Xu group synthesized a series of naphthalene-based peptides NapFF, NapFFKK, NapFFFKK, NapFFOO, and NapFFK′K′ (K′ refers to ε-aminolysine).¹⁰³ These molecules assemble into three-dimensional entanglements of densely packed nanofiber structures driven by π–π stacking between naphthyl and phenylalanine, hydrophobic interactions, and hydrogen bonding of cationic side chains (Fig. 5b). Compared to other cationic naphthalene variants, the β-sheet configuration of NapFFK′K′ has the strongest signal, indicating that the monomers are more regularly arranged. Overall, molecular assembly, hydrogelation, and antimicrobial efficacy can be synergistically governed by the side chain length of K, O, and ε-linked K. In another example, the amino acid F was partially or totally replaced by W, and the phosphorylated tyrosine (Yp) was also incorporated, giving four tetrapeptides Nap-WWKYp, Nap-FWKYp, Nap-WFKYp, and Nap-FFKYp.¹⁰⁷ The Yp residue may undergo in situ dephosphorylation catalyzed by overexpressed alkaline phosphatase (ALP), and thus trigger the self-assembly and the formation of supramolecular materials, which is well known as enzyme-instructed self-assembly (EISA). Since ALP is often overexpressed in pathological sites, the EISA approach could prevent off-target aggregation and premature self-assembly in healthy tissues, thereby minimizing the risk of systemic toxicity. After the enzyme cleaved the phosphate group, Nap-FWKY self-assembled into long and flexible left-handed twisted nanoribbons, while Nap-WWKY and Nap-WFKY self-assembled into right-handed twisted nanoribbons. In contrast, Nap-FFKY without W residues self-assembled into straight nanofibers. Such differences were also verified by their secondary structures, where Nap-FFKY, different from W-containing sequences, exhibited a typical β-sheet configuration. Although replacing F residues with W could change the peptide conformation, they still tended to self-assemble into ordered structures, resembling β-sheets, through intermolecular interactions. Using a similar strategy, Liang et al. designed an enzymatic Nap–peptide conjugate Nap-FFK(Ada)-Tyr(H₂PO₃)-OH (Nap-FYp-Ada).¹⁰⁴ This conjugate contains a structural motif (Nap-FF), lipophilic adamantane (Ada) conjugated onto the lysine side chain, and a phosphotyrosine residue that can be activated by ALP (Fig. 5c). Upon contacting the Staphylococcus aureus (S. aureus) membrane surface, Nap-FYp-Ada will undergo dephosphorylation, and immediately self-assemble in situ into nanofibers at the membrane interface, compromising membrane integrity and leading to the leakage of the bacterial membrane. Moreover, Nap-FYp-Ada exhibits a lower MIC against S. aureus compared to the self-assembled Nap-FY-Ada and non-self-assembling Nap-AYp-Ada, demonstrating the pivotal role of EISA in the antibacterial mechanism.

Artificial intelligence (AI) also presents a transformative technology in AMP discovery, enabling rapid exploration of the vast peptide sequence landscape and generating extensive libraries of novel AMP candidates.^108–110 Wang and his co-workers developed a deep learning framework called TransSAFP, which integrated a pretrain-transfer learning architecture with 11 classes of N-terminal self-assembling motifs to enhance peptide self-assembling propensity and achieve high-precision antimicrobial activity prediction on sparsely annotated data (Fig. 6).¹¹¹ Most of the self-assembling functional peptides (SAFPs) exhibited CAC values below 100 μg mL⁻¹. Cryo-EM showed SAFPs forming a variety of assembly morphologies, including nanoaggregates, nanofibers, worm-like structures, nanonets, and sheets. They further experimentally confirmed the successful screening of 121 novel self-assembling AMPs, demonstrating an 86% design success rate. In a murine acute enteric infection model of Salmonella typhimurium, the peptide P45 (NAP-MKKWMKLLRHITSP) demonstrated comparable therapeutic efficacy to ciprofloxacin. After 30 serial passages of Salmonella typhimurium, no acquired resistance to P45 was observed, whereas the MIC of ciprofloxacin increased 256-fold. Moreover, P45 nearly completely removed established biofilms, while approximately 90% of the biofilm biomass persisted following ciprofloxacin treatment.

Fig. 6 Supramolecular AMP design via AI. (a) AI-guided design of novel SAFPs. (b) Determination of the CAC for SAFPs. (c) Cryo-EM images showing that SAFPs can self-assemble into distinct nanostructures. Reproduced with permission.¹¹¹ Copyright 2025 Springer Nature.

Pyrene is also used to promote the formation of nanoassemblies, which could even provide stronger π–π interactions and hydrophobic forces compared with naphthalene. For example, Li and co-workers designed a biomimetic binding-induced fibrillogenesis peptide (bis-pyrene-KLVFF-WHSGTPH, named BFH) and a control peptide (bis-pyrene-KAAGG-WHSGTPH, named BAH).¹¹² Upon dissolution, the peptides first aggregated into nanoparticles due to the strong hydrophobic collapse of two pyrenes. After binding to Mycobacterium tuberculosis or Bacille Calmette–Guérin (BCG) via receptor-mediated interactions, the peptide assemblies transformed into nanofibers. In contrast, the control peptide remained as nanoparticles, indicating the synergistic role of receptor binding and the KLVFF motif in driving this nanoparticle-to-nanofiber transition. Consequently, the resulting BFH fibrous network captured BCG in situ, effectively resisting macrophage phagocytosis and preventing infection.

3.4. Cholesteric peptides

Cholesterol, a ubiquitous component of mammalian cell membranes, can also serve as a hydrophobic auxiliary to drive the formation of supramolecular materials, and enhance the affinity to lipid bilayers.^113,114 In one typical example, the Yang group designed a self-assembling cholesteric peptide, TAT-PEG-b-Chol, where the cell-penetrating TAT motif (YGRKKRRQRRR) is linked to a cholesteryl (Chol) moiety via a polyethylene glycol (PEG) spacer.¹¹⁵ This cholesteric peptide can self-assemble into nanoparticles with diameters less than 200 nm, which can function as delivery vehicles for antibiotics. In another work, they further introduced the cationic segment R6 as an antimicrobial fragment inserted between the cholesterol and TAT segments.¹¹⁶ The peptide CG₃R₆TAT readily formed core–shell nanoparticles with a hydrophobic cholesterol core, a hydrophilic cationic peptide shell, and a TAT moiety oriented toward the external environment (Fig. 7a). Due to the high surface charge density, these nanoparticles can fight clinically isolated Cryptococcus neoformans with minimal inhibitory concentrations (MICs) significantly lower than that of fluconazole. Furthermore, subsequent studies have determined that the cationic peptide-based nanoparticles can penetrate the blood–brain barrier (BBB), exhibiting comparable efficacy in treating meningitis to amphotericin B and avoiding the associated hepatotoxicity and nephrotoxicity.¹¹⁷

Fig. 7 Supramolecular AMP design of cholesteric peptides. (a) The molecular model and SEM images of CG3R6TAT nanoparticles. Reproduced with permission.¹¹⁶ Copyright 2009 Springer Nature. (b) Chemical structure and characterization of a cholesteric peptide. Reproduced with permission.¹¹⁸ Copyright 2018 American Society for Microbiology.

Zhang and his colleagues designed a self-assembling cholesteric peptide, DP7-C, where the AMP DP7 (VQWRIRVAVIRK) was linked to a Chol group via a succinic acid spacer.¹¹⁸ The addition of the cholesterol group adjusted the hydrophilic–hydrophobic balance, thereby driving the formation of nanostructures. DP7-C can self-assemble in both aqueous solution and culture media, exhibiting a low critical micelle concentration (CMC). In water, DP7-C formed homogeneous micelles with an average diameter of approximately 36 nm (Fig. 7b). Compared with the original peptide, the supramolecular assembly of the cholesterol-conjugated peptide not only killed bacteria more effectively, but also served as a carrier and immune adjuvant to promote the therapeutic effectiveness of cancer by loading neoantigens and mRNA.^119,120

3.5. Self-assembling polypeptides

Polypeptides are another representative class of AMPs. To create self-assembling polypeptides, a series of hydrophobic polymers were conjugated with hydrophilic AMPs. By regulating their composition and architecture, these conjugates can self-assemble into diverse supramolecular nanostructures that exploit the synergistic functions of both components. This strategy offers a flexible platform for designing supramolecular peptide-based antimicrobials with strong antibacterial efficacy and expands therapeutic capabilities.

Amphiphilic AMP–polymer conjugates can spontaneously form micelles in which hydrophobic polymers aggregate in the core and peptide segments face the water. This micellar organization concentrates the antimicrobial peptides locally, thereby enhancing their membrane-disruptive activity and overall efficacy. In one example, the Du group reported PLLA₃₁-b-poly(Phe₂₄-stat-Lys₃₆), which self-assembles into core–shell micelles with the PLLA block in the core and the polypeptide block decorating the surface (Fig. 8a).¹²¹ The micelles exhibited an average diameter of 70 ± 6 nm and a critical micelle concentration of 13.2 μg mL⁻¹. TEM studies revealed that these micelles first adsorb onto bacterial membranes, induce membrane disruption, and ultimately cause cytoplasmic leakage in both E. coli and S. aureus. In subsequent work, they designed dual-corona vesicles through co-assembly of two block copolymers, PCL₂₂-b-poly(Lys₁₅-stat-Phe₁₀) and PCL₃₅-b-PEO₂₂.¹²² The PEO corona prevents protein adsorption and promotes deep penetration into the biofilm extracellular polymeric substances, while the poly(Lys-stat-Phe) corona provides cationic surface charge and intrinsic broad-spectrum antibacterial activity. TEM and DLS revealed that these dual-corona vesicles (315 nm) are larger than single-corona counterparts, confirming successful co-assembly. Encapsulation of antibiotics in these dual-corona vesicles halved the required dose to eradicate E. coli or S. aureus biofilms. In a rat periodontitis model, administration of the vesicles markedly reduced dental plaque and inflammation, demonstrating their in vivo efficacy. In another study, Ji and co-workers designed pH-sensitive nanoparticles (anti-CD54@Cur-DA NPs) assembled from curcumin-loaded PAMAM dendrimers, 2,3-dimethyl maleic anhydride-modified biotin-PEG-PLys, and anti-CD54.¹²³ Under neutral pH, Cur-DA NPs presented a diameter of approximately 90 nm and carried a ζ potential of −5.1 mV. But within the acidic biofilm microenvironment, they rapidly shrank to about 13 nm and reversed their surface charge to +20 mV (Fig. 8b). This adaptive size reduction and charge inversion facilitated deep penetration of the nanoparticles into the biofilm matrix.

Fig. 8 Supramolecular AMP design of polypeptides. (a) Chemical structure of a polypeptide which can self-assemble into micellar nanostructures. Reproduced with permission.¹²¹ Copyright 2016 American Chemical Society. (b) pH-dependent variations in the hydrodynamic diameter and ζ-potential of Cur-DA nanoparticles. Reproduced with permission.¹²³ Copyright 2023 American Chemical Society. (c) TEM images and the synthesis strategy of star-shaped AMP–polymer nanoparticles. Reproduced with permission.¹²⁴ Copyright 2016 Springer Nature.

Branched polypeptide–polymer conjugates often exhibit enhanced antimicrobial activity compared with their linear analogues, while maintaining good biocompatibility, biodegradability and versatile biological functionality.¹²⁵ For instance, Qiao et al. sequentially initiated the polymerization of NCA-lysine and NCA-valine initiated by a PAMAM dendritic core, and developed a class of antimicrobial agents, termed “structurally nanoengineered AMP polymers” (SNAPPs) (Fig. 8c).¹²⁴ Due to the star-shaped nanostructure that provides high local charge density and AMP mass payload, SNAPPs proved highly effective in vivo against Acinetobacter baumannii and did not induce resistance even after 600 generations of growth (over a period of 24 days). Cryo transmission electron microscopy (Cryo-TEM) and 3D structured illumination microscopy revealed that SNAPPs kill bacteria by a multi-modal mechanism involving outer membrane destabilization, uncontrolled ion flow across the cytoplasmic membrane, and induction of apoptosis-like cell death.

3.6 Co-assembling peptides

The biological function of AMPs is closely associated with their primary and secondary structures. When conjugated with an assembly-directing structural moiety, the conformation and bioactivity of AMPs may inevitably suffer substantial variations. Supramolecular co-assembly offers an innovative approach for fabricating nanoscale architectures through the introduction of additional monomers capable of forming co-assemblies together with AMP monomers.^126–128 By modifying the additional monomer, the co-assembly system can also exhibit chemical diversity and functional complexity. Therefore, the appropriate interplay between the multiple components plays a vital role in determining the co-assembly process, facilitating the formation of highly stable and well-defined supramolecular antimicrobial nanostructures.

Given that most of the AMPs carry positive charges, the straightforward incorporation of auxiliary monomers with opposite charges can effectively facilitate their co-assembly through electrostatic interactions. For example, Ma et al. designed oppositely charged peptides based on this strategy, including the positively charged bactericidal peptide PCBP [C₁₄-(FKF)₃-R₈-NH₂] and the negatively charged attenuating peptide NCAP [PEG₈-(FDF)₃].¹²⁹ In their design, the R₈ segment endows PCBP with a positive charge and bacterial targeting capability, while the PEG₈ moiety enhances the biocompatibility of the co-assembled nanostructures. The (FKF)₃ and (FDF)₃ segments leverage electrostatic attractions between K and D, in conjunction with π–π interactions, to reinforce peptide assembly. The two monomers first get closer via attractive forces between their opposite charges, and the assembly is further driven synergistically by hydrogen bonding, π–π interactions, and hydrophobic forces, resulting in nanofibers with β-sheet structures. A similar recent study also co-assembled a cell-penetrating peptide R₈ with an anionic surfactant sodium dodecyl sulfate (SDS).¹³⁰ They found that different R₈/SDS molar ratios (such as 4 : 1, 2 : 1, 1 : 1) induced a transition from short and dispersed worm-like micelles to layered structures, demonstrating the controllability of the assembly morphology of the aggregation unit (Fig. 9a). Under the condition of higher positive charge enrichment (with the molar ratio of R₈/SDS being 4 : 1), the self-assembly is jointly dominated by strong electrostatic interactions between the guanidine group of R₈ and the sulfate group of SDS, as well as hydrogen bonding interactions. The excessive positive charges provide repulsive forces and maintain a high hydrophilic–hydrophobic balance, thereby forming short and dispersed worm-like micelles. With the increase of the SDS ratio (R₈/SDS = 2 : 1), more guanidine groups are paired and then hydrophobic interactions between the alkyl chains of SDS gradually become dominant, promoting the formation of layered structures in the system.

Fig. 9 Supramolecular AMP design of co-assembling peptides. (a) Variation in charge ratio tuned the nanostructures and antibacterial activity. Reproduced with permission.¹³⁰ Copyright 2025 Wiley. (b) Co-assembled system incorporating structural motif Fmoc-F and bioactive motif Fmoc-L formed an antimicrobial hydrogel. Reproduced with permission.¹³¹ Copyright 2015 Wiley.

As mentioned above, Fmoc-F is known to self-assemble into nanofibers and form antibacterial supramolecular hydrogels. To enhance its antibacterial efficacy, the Chen group employed co-assembly strategies by incorporating structurally similar components, such as Fmoc-X (where X represents G, I, V, A, or L).¹³¹ Through the strong aromatic interactions of the common motif Fmoc, these monomers can still co-assemble into nanofibers. To validate this assembly behavior, molecular dynamic (MD) simulations were carried out to examine the aggregation of various Fmoc-amino acids in water. In the Fmoc-F and Fmoc-L systems, the simulations revealed spontaneous formation of an interconnected 3D nanofiber network. In contrast, other five Fmoc derivatives lacking an aromatic phenyl side chain assembled only into discrete, pillar-like fibrils. Notably, co-assembly of Fmoc-F and Fmoc-L yielded supramolecular hydrogels with enhanced antibacterial activity against Gram-positive bacteria (Fig. 9b). In this system, Fmoc-F serves as the primary structural motif, while Fmoc-L contributes to antimicrobial functionality via hydrophobic interactions and leucine-mediated disruption of bacterial membranes. Later, Gazit et al. developed an antibacterial hydrogel via Fmoc-F/K co-assembly, combining π-stacked nanofibers with lysine's cationic charge to enable broad-spectrum efficacy against both Gram-positive and Gram-negative bacteria.¹³² Overall, this co-assembly approach can create multi-component systems with additional functionalities tailored for diverse applications, thereby improving overall performance.

4. Applications and superiorities of antimicrobial peptide assemblies

Based on the design principle of self-assembling peptides, a series of supramolecular AMPs with diverse well-defined nanostructures have been developed. Through self-assembly, AMPs acquire nanoscale controllable structural features that effectively protect them from enzymatic degradation and reduce rapid clearance by endothelial barriers and immune cells, thereby prolonging their half-life and enhancing therapeutic efficacy. Additionally, self-assembly increases the local cation density on the surface of the nanostructures, thereby strengthening the electrostatic interaction with the negatively charged bacterial membrane and ultimately promoting membrane disruption.¹¹⁶ Nanostructures may offer a larger surface area and higher aspect ratio, promoting multivalent binding with pathogens. These results endow the assemblies with a stronger membrane-binding ability compared to monomeric peptides.¹³³ Moreover, the filamentous supramolecular assemblies can further entangle to form networks, which can physically entrap and immobilize bacteria, thereby reducing adhesion and preventing subsequent invasion.¹³⁴ Importantly, the dynamic and reversible nature of supramolecular assemblies enables controlled release of peptide monomers in specific sites to maintain effective concentrations over extended periods. In particular, peptide-based hydrogels can encapsulate multiple therapeutics and release them in a controlled manner, enhancing antimicrobial efficacy and supporting combination therapy strategies.¹³⁵ Finally, self-assembly provides a versatile platform for incorporating functional modifications, such as targeting ligands or stimuli-responsive elements, which further optimize AMP activity and delivery.¹³⁶

Due to the unique features of supramolecular assemblies, the peptide-based antimicrobials demonstrate diverse mechanisms of action and show promising potential for various applications (Fig. 10). In the recent decade, numerous studies have revealed the promising potential of peptide assemblies to address challenges encountered by small molecule AMPs.^137–142 To highlight the applications and superiorities of antimicrobial peptide assemblies, in this section, we will first introduce the effects of self-assembly and morphology on the antimicrobial properties of supramolecular AMPs. Subsequently, examples of bacterial inhibition achieved through biomimetic capturing mechanisms employing supramolecular networks will be summarized. In addition, supramolecular peptide-based materials will be discussed as novel drug delivery systems for the controlled release of antibiotics or small molecule AMPs. To make it clear, we have summarized the sequence, assembly condition, self-assembled morphology and ultimate applications of self-assembling AMPs in Table 1 and Table 2, where we have focused on in vitro and in vivo experiments, respectively.

Fig. 10 Applications and advantages of supramolecular antimicrobial peptide assemblies. (a) Possible modes of antibacterial action of supramolecular peptide nanostructures via interactions with bacterial membranes. (b) Biomimetic peptide networks capture and immobilize bacteria. (c) Peptide assemblies encapsulate antibiotics, AMPs or metal nanoparticles for controlled release and extended retention at infection sites.

Table 1 Summary of the peptide sequence, assembly condition, self-assembled morphology and in vitro biological activity for supramolecular AMPs

Sequence	Assembly condition	Self-assembled morphology	Biological activity	Ref.
a Lowercase denotes D-amino acids.
Ac-A9K-NH2	Aqueous solution	Nanorods	Antimicrobial activity	62
			Membrane permeabilization
			Low hemolysis
PLLA31-b-poly(Phe24-stat-Lys36)	Deionized water	Nanomicelles	Broad-spectrum antimicrobial activity	121
FF	Ultra-pure water	Nanotubes	Anti-Gram-negative bacterial infections	74
			Membrane disruption
			Biocompatibility toward HEK293 and HaCaT cells
Np-I3RRHK	Buffer solution	Nanoribbons	MRSA bactericidal activity	143
Np-RI3HKR			Biofilm inhibition
Np-I3HKRR
KRWHWWRRHWVVW-NH2	Aqueous solution	Nanofibers	Specific killing of M. tuberculosis	65
			Low cytotoxicity toward NL20, THP-1, RAW 264.7, and HUVEC cells
VKVRVRVRVpPTRVRVRVKV^a	Buffer solution	Nanofibers	Antimicrobial activity	78
			Cytocompatibility with mesenchymal C3H10t1/2 stem cells
H2N-(CH2)4CONH-Phe-CONHC12	Aqueous solution	Nanofibers	Broad-spectrum antimicrobial activity	89
			Low hemolytic toxicity
			Protease-resistant (proteinase K and chymotrypsin)
C16-V4R4^a	Ultrapure water	Nanofibers	Broad-spectrum antimicrobial activity	91
NapFFKK	Deionized water	Nanofibers	Antibiofilm activity	103
Nap-FWKYp	Conversion to nanofibers upon ALP catalysis	Nanofibers	Bacterial flocculation	107
			Broad-spectrum antimicrobial activity
Bis-Pyrene-KLVFF-WHSGTPH	Nanoparticles binding M. tuberculosis and transforming into nanofibers	Nanofibers	M. tuberculosis entrapment	112
			Prevention of macrophage invasion
Ac-VVVVVVKKK-NH2	PAO-induced conversion of nanoparticles into nanofibers	Nanofibers	Antimicrobial activity	64
			Low cytotoxicity to NIH 3T3 cells
FLGALFRALSRLL-NH2	Buffer solution	Nanofibers	Antimicrobial activity	144
			Low hemolysis
Nap-FFYp-OH	After ALP enzymed to nanofibers	Nanofibers	Antibacterial activity against E. coli	145
C16-V4K4G(AKKARA)2	Deionized water	Nanofibers	Antibacterial properties against both Gram-positive and Gram-negative bacteria	146
NapFF-GG-SSGGGGSSGGGGH-OH	S. aureus surface protein binding-driven nanofiber self-assembly	Nanofibers	Cytocompatibility with human cells	147
			Prevents bacterial invasion and biofilm formation

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Table 2 Summary of the peptide sequence, assembly condition, self-assembled morphology, antibacterial effect and animal model for supramolecular AMPs

Sequence	Assembly condition	Self-assembled morphology	Antibacterial effect	Animal model	Ref.
a Lowercase denotes D-amino acids.
kQrWlWlW^a	In synthetic membranes	Nanotubes	Broad-spectrum antibacterial activity	Lethal MRSA peritonitis model	47
Lev/Dex-SA-RGD	Buffer solution	Nanotubes	Broad-spectrum antibacterial activity	S. aureus-induced endophthalmitis model	148
Fmoc-FFF-YGRKKRRQRRR	Buffer solution	Nanorods	Broad-spectrum antibacterial activity	S. aureus-induced peritonitis sepsis model	149
Nap-FFF-YGRKKRRQRRR
C14-(H3F)3H3-K(PEG8)-QRKLAAKLT-NH2	Nanofibers transform into nanoparticles upon contact with biofilm	Nanoparticles	Anti-P. aeruginosa activity	Drug-resistant P. aeruginosa biofilm infection model	25
FFPFFKKRAKKFFKKPRVIGVSIPF	Aqueous solution	Nanoparticles	Anti-Gram-positive bacterial infections	Lethal E. coli peritonitis model	29
				E. coli-infected mouse wound model
C12-GRWRRFWGKAKRGIKKHGV	Buffer solution	Nanoparticles	Broad-spectrum antibacterial activity	A mouse model of skin wound infection	90
Chol-G3R6YGRKKRRQRRR	Deionized water	Nanoparticles	Broad-spectrum antibacterial activity	S. aureus-induced rabbit meningitis model	116
ATCYCRTGRCATRESLSGVCEISGRLYRLCCRK-C14	Deionized water	Nanoparticles	Broad-spectrum antibacterial activity	Lethal E. coli sepsis model	150
				MRSA-infected mouse wound model
WRWRWY	Tyrosinase oxidation	Nanoparticles	E. coli and S. aureus	S. aureus-infected mouse wound model	151
RFRRLRKKWRKRLKKI-mPEG1000	Aqueous solution	Nanomicelles	Broad-spectrum antibacterial activity	A mouse acute lung injury model	152
WWKKWKKWW	Buffer solution	Nanomicelles	Broad-spectrum antibacterial activity	Subcutaneous catheter mouse model	153
FKF	Aqueous solution	Nanofibers	Broad-spectrum antibacterial activity	P. aeruginosa-infected rat wound model	77
VKVKVRVKVpPTKVKVRVŸV-NH2^a	1.0 wt% gel in buffer solution	Nanofibers	MRSA and S. epidermidis	Titanium implant infection	67
C12-G(IIKK)2I-NH2	Buffer solution	Nanofibers	Broad-spectrum antibacterial activity	MRSA abscess model in mice	87
Nap-FFK(Ada)-Tyr(H2PO3)-OH	Conversion to nanofibers upon ALP catalysis	Nanofibers	Anti-Gram-positive bacterial infections	S. aureus-infected mouse wound model	104
Bip-FFKWKLFKK	Buffer solution	Nanofibers	Disrupts membrane integrity and depolarizes membrane potential	MRSA-infected rabbit osteomyelitis model	154
bis-pyrene-KLVFF-RLYLRIGRR	Nanoparticles bind to S. aureus cell walls and transform into nanofibers	Nanofibers	Anti-Gram-positive bacterial infections	MRSA-induced bacteremia mouse model	134
LKLKLKLTAKLKLKL-NH2	Buffer solution	Nanofibers	Capture and killing of E. coli and S. aureus	E. coli-infected peritonitis model	155
LKLKLKVDPPAKLKLKL-NH2
(FQFG)4-SGS-RKVRGPP	Aqueous solution	Nanofibers	Capture of bacteria and activation of antibacterial immune responses	E. coli-infected peritonitis-sepsis model	156
PFKLSLHL-NH2	Buffer solution	Nanofibers	Broad-spectrum antibacterial activity	MRSA-infected mouse wound model	157
IKFQFHFD	Self-assembly at pH 7.4 and disassembly at pH 5.5	Nanofibers	Broad-spectrum antibacterial activity	MRSA biofilm-infected diabetic ulcer mouse model	158
Ac-KPVFQFLFHE-NH2	Self-assembly at pH 7.4 and disassembly at pH 5.5	Nanofibers	Anti-Gram-positive bacterial infections	S. aureus-infected mouse wound model	135
Chitosan-GPLGVRGC-KLAK	Nanoparticles are cleaved by gelatinase to form nanofibers	Nanofibers	S. aureus and P. aeruginosa	S. aureus-infected mouse model	159

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4.1. Assembly-induced enhancement of antimicrobial activity

Unlike unimolecular AMPs, supramolecular assemblies shield degradable peptides inside of the nanostructures via tight molecular packing, which prevents the in vivo degradation of peptides and improves biostability. Moreover, the formation of nanostructures may amplify their interactions with bacterial cell surfaces, significantly increasing antibiotic efficacy. Therefore, the supramolecular strategies have been recognized as an elegant platform for designing antibiotic materials with optimized biostability and targeted antimicrobial activity.

The antimicrobial activities can be altered upon self-assembly. For example, the Cheng group designed a fluoropeptide amphiphile (R6F) by conjugating a C8F13 fluorous tag (referring to eight carbon atoms and thirteen fluorine atoms) to a hexa-arginine (R₆) oligopeptide via a disulfide spacer (Fig. 11a).¹⁶⁰ Fluorolipids are bioinert, have low surface energy, and possess both hydrophobic and lipophobic properties. Their low surface energy enhances cell membrane binding, while lipophobicity minimizes membrane retention. Compared to parent oligo(lysine)s and oligo(arginine)s, the fluorinated R₆ cell-penetrating peptide can self-assemble into nanoparticles, significantly enhancing bacterial membrane permeability and disruption and improving the antibacterial effect against MRSA. To further confirm the mechanism of membrane disruption of antimicrobial nanoparticles, they created artificial bacterial membranes through synthetic unilamellar vesicles composed of DOPC, DOPG, and DOPE in a 4 : 3 : 3 molar ratio. These vesicles were labelled with the fluorescent dye Dil and subsequently incubated with R6F. Upon treatment, a gradual reduction in Dil fluorescence was observed, accompanied by the rapid diffusion of the membrane-impermeable dye calcein into the vesicle interior. These findings indicated that R6F effectively disrupts the vesicle membrane integrity. In another study, Lu et al. designed a class of constitutionally isomeric heptapeptides, with Np-I₃RRHK self-assembling into rigidly twisted nanoribbons, while Np-RI₃HKR and Np-I₃HKRR formed relatively flexible ones.¹⁴³

Fig. 11 Supramolecular AMPs with diverse morphologies exhibit high antimicrobial activity. (a) Schematic of a library screening for fluoro-lipopeptides against MRSA-mediated sepsis and wound infections. Reproduced with permission.¹⁶⁰ Copyright 2024 Wiley. (b) Design and performance of self-assembled AMPs with dual functions in cell penetration and antibacterial activity. Reproduced with permission.¹⁴⁹ Copyright 2025 American Association for the Advancement of Science. (c) Schematic illustration of the self-assembly behavior and structural transformation of pH-responsive supramolecular AMPs. Reproduced with permission.²⁵ Copyright 2023 Wiley. (d) Peptide K6 nanoparticles demonstrate superior antibiofilm efficacy over gentamicin and safely eradicate P. aeruginosa–S. aureus biofilms in a murine model. Reproduced with permission.¹⁵³ Copyright Proceedings of the National Academy of Sciences.

Among these, Np-I₃RRHK exhibited the strongest antibacterial efficacy against the planktonic bacteria. Co-incubation of MRSA biofilms with Np-I₃RRHK resulted in significant decreases in biomass, thickness, and density, demonstrating effective disruption of mature biofilms. These differences in antibacterial efficacy may be attributed to the positively charged amino acid residues presented on the surfaces of the peptide assemblies. MD simulations further confirmed that the Np-I₃RRHK component exhibits the highest positive charge density per unit length, which correlates with its superior antibacterial activity. More recently, Shan et al. developed self-assembling AMPs, F3FT (Fmoc-FFF-YGRKKRRQRRR) and N3FT (Nap-FFF-YGRKKRRQRRR), derived from the cell-penetrating peptide TAT, which can separately assemble into nanorods and nanoparticles (Fig. 11b). Compared with the TAT peptide, F3FT and N3FT exhibited potent antibacterial activity against Gram-positive bacteria, with enhanced cell penetration. Compared to melittin, F3FT and N3FT showed reduced hemolysis and cytotoxicity. Notably, F3FT demonstrated the highest selectivity index (SI) calculated from IC₅₀/MIC. These peptides can penetrate cells via macropinocytosis and clathrin-mediated endocytosis, respectively.¹⁴⁹ The nanoassemblies combat intracellular bacteria through a dual mechanism: disrupting bacterial cell membranes and inducing excessive accumulation of reactive oxygen species.

To enhance the bioavailability and in vivo stability of HD5 (ATCYCRTGRCATRESLSGVCEISGRLYRLCCR), Lei et al. myristoylated its N-terminus and C-terminus, respectively.¹⁵⁰ Due to the increased hydrophobicity, both N-terminus and C-terminus modified molecules could assemble into nanospherical structures. Compared with the parent and N-terminus modified HD5, the C-terminus myristoylated HD5 (HD5-myr) demonstrated broad-spectrum and significantly enhanced bactericidal activity against Gram-positive and Gram-negative bacteria in vitro, which may be attributed to the formation of nanostructures that present a substantially higher local density of charged and hydrophobic residues. In contrast to unmodified HD5, which did not affect the integrity of the inner membrane of Gram-negative bacteria, HD5-myr exerted its bactericidal effect by disrupting the entire bacterial membrane and cell wall, potentially facilitating the penetration of co-administered antibiotics. Moreover, HD5-myr effectively reduced systemic bacterial burden and inflammatory damage in animal models while exhibiting excellent in vivo safety and resistance to proteolytic degradation. Using a similar strategy, the serum- and protease-sensitive AMP T9W (RFRRLRKKWRKRLKKI) was synthesized and modified with PEG (1000 Da) at its N-terminus (NT9W₁₀₀₀) and C-terminus (CT9W₁₀₀₀), respectively. This modification promoted the self-assembly of T9W into nanostructured antimicrobial micelles, which exhibit significantly improved pharmacological properties.¹⁵² Compared with the monomeric T9W, the in vivo stability of the nanoparticles was significantly enhanced. In order to investigate the effect of the assembly on the protease resistance of T9W that contains trypsin cleavage sites, they incubated trypsin with T9W or CT9W₁₀₀₀ for 1 hour, and found that the antibacterial activity of CT9W₁₀₀₀ against P. aeruginosa remained similar and the retention rate was greater than 90%, while T9W was completely degraded and lost its antibacterial activity. This can be attributed to the encapsulation of core amino acids by the core–shell structure of the nanoparticles, reducing the contact and cleavage by trypsin. Additionally, compared with T9W, CT9W₁₀₀₀ has a higher average antibacterial activity against P. aeruginosa and an expanded antibacterial spectrum. The micelles formed by CT9W₁₀₀₀ can tightly adhere to the surface of the bacterial outer membrane (OM), demonstrating a stronger membrane disruption ability.

In addition to incorporating nonpeptide auxiliaries, integrating specific peptide segments into the AMP backbone can also promote self-assembly. For example, Lan and co-workers enhanced the self-assembly capability of the unassembled α-helical AMP OH20 (KKRAKKFFKKPRVIGVSIPF) by appending four different peptide sequences (the insertion of FFPFF, KLFFAE, QEFFQFFKQAG, and QEFFQFFKQAA sequences is denoted as P1, P2, P3, and P4, respectively) to its N-terminus.²⁹ Owing to the different secondary structures imparted by these insertions, the resulting OH20-derived peptides self-assembled into nanostructures with varied morphologies in aqueous solution. Specifically, P1 self-assembled into nanoparticles with a diameter of 200 nm, while P2 formed linear fibers with a width of about 700 nm. Among them, the P1 nanoparticles exhibited superior antibacterial activity and could synergize with specific antibiotics.

Nanofibers and nanotubes with high aspect ratios can promote bacterial morphological disruption and hinder bacterial movement and migration.^140,161 In a seminal study, Ghadiri et al. designed cyclic D,L-α-peptides with alternating D- and L-amino acids, resulting in a flattened ring conformation.⁴⁷ Upon interacting with bacterial membranes, these peptides (e.g., kQrWlWlW, kKkWlWlW, rRkWlWlW) self-assembled into β-sheet-like nanotubes, which enhanced membrane permeability and promoted the transport of ions and small molecules. In another case, Yang et al. developed a phosphotripeptide (Nap-FFpY), which was the first example of EISA of peptides in a living organism to inhibit the growth of bacteria.¹⁴⁵ After the treatment of ALP, the dephosphorylated Nap-FFY self-assembled in aqueous solution and formed supramolecular nanofibers, and ultimately induced hydrogelation. They further incubated Nap-FFpY with E. coli that can overexpress phosphatase, and observed the intracellular accumulation of Nap-FFY. When enough Nap-FFY accumulates inside the bacterial cell, it can self-assemble into nanofibers that inhibit the growth of E. coli. The Thomas group designed a self-assembling peptide (ACA-PA, C₁₆-V₄K₄G(AKKARA)₂) that contains a heparin-binding Cardin motif (AKKARA) and a self-assembly motif (CVK-PA, C₁₆-V₄K₄).¹⁴⁶ Below its CMC, the ACA-PA peptide molecule showed a dose-dependent effect against Gram-positive bacteria. As the peptide concentration increased above CMC, ACA-PA formed a cylindrical structure driven by the hydrophobicity of palmitic alkyl chains and the hydrogen bonding of V₄. Notably, ACA-PA nanofilaments demonstrated largely enhanced antibacterial efficacy compared to both Cardin and CVK-PA, validating the superiorities of supramolecular self-assembly.

Similarly, Martin and his colleagues designed a series of cationic PAs by tuning the hydrophobic alkyl chain length (C₁₂–C₂₀) and cationic peptide sequence (e.g., K, O, R).¹⁶² These PAs can form diverse nanostructures including micelles, nanofibers, and twisted ribbons. Among these, micelle-forming PAs (e.g., PA4, C₁₈K₅) exhibited the best antibacterial activity, while nanofiber-forming variants (e.g., PA15, C₁₈V₃K₅) showed significantly reduced efficacy. This activity disparity is possibly linked to the supramolecular stability of nanostructures. Micelles with weaker intermolecular forces enable monomer release to disrupt bacterial membranes, while nanofibers maintain structural integrity through the strong hydrogen bonds in the β-sheet regions, limiting membrane interactions. The study further revealed that balanced hydrophobic–hydrophilic interactions and positive charge density could govern micellar antibacterial potency, although excessive hydrophobicity (e.g., PA5, C₂₀K₅) may increase mammalian cytotoxicity. In a separate work, the Ma group developed a pH-responsive self-assembling peptide [C₁₄-(H₃F)₃H₃-K(PEG₈)-QRKLAAKLT-NH₂].²⁵ Variations in pH can induce protonation or deprotonation of histidine residues, resulting in a morphological transition of the assemblies from nanofibrous structures to vesicular nanostructures (Fig. 11c). In normal physiological pH (7.4), the peptide can assemble into nanofibers, thereby enhancing its biological stability and prolonging circulation time. Upon encountering biofilm areas (pH 5.0), the histidine residue was protonated, leading to electrostatic repulsion between peptide monomers and a morphological transition from nanofibers to nanoparticles in situ. The transition resulted in a significant increase in local charge density and hydrophobicity, which in turn enhanced the ability to penetrate biofilms and interact with bacterial cell membranes, thereby improving its antibacterial properties. A single intravenous dose of 10 mg kg⁻¹ administered in vivo resulted in a circulation half-life of 103.1 ± 13.8 minutes. Following five consecutive days of administration at doses of 10, 20, or 30 mg kg⁻¹, the treated mice showed no pathological alterations in liver or kidney tissues, demonstrating excellent biocompatibility. Moreover, even after 48 hours, high levels of peptide nanoassemblies remained detectable within the biofilm-infected regions of the mice, indicating the ability of these nanostructures to exert prolonged bactericidal effects in vivo.

However, it is worth noting that chemical modifications to create self-assembling AMPs may sometimes lead to a reduction in their antimicrobial activity. For example, Vincent and colleagues designed a series of self-assembling peptides based on the parent sequences PTP7 (FLGALFKALSKLL) and CL1 (FLGALFRALSRLL), including analogues with C- and N-terminally uncapped (PTP7U, CL1U), C-terminally capped (PTP7-NH₂, CL1-NH₂), and fully capped (PTP7C, CL1C).¹⁴⁴ The relationship between stability of the resulting supramolecular assemblies and their corresponding antibacterial efficacy was systematically investigated. They examined the self-assembly morphology of CL1C by cryo-TEM, and found that the fully capped peptides exhibited pronounced α-helical signatures and further assembled into bilayer nanotubes held together by hydrophobic inter-helix contacts. On the other hand, the self-assembly capability of the partially capped and uncapped analogues decreased successively. However, the partially capped peptides exhibited the strongest antimicrobial activity, followed by the uncapped variants, whereas the fully capped peptides showed no detectable antibacterial activity within the tested concentration range. These results indicated that structural modifications which enhanced the stability of filamentous assemblies led to suppressed membranolytic activity. Conversely, more dynamic assembly structures resulted in enhanced bacterial cell lysis. In a recent study, Zheng et al. developed a series of cecropin A (Ce1–8, KWKLFKKI) derivatives with fatty acid chains ranging from C₂ to C₁₈, which self-assembled into spherical nanoparticles with propensity increasing as the alkyl chain length increased.¹⁶³ Among these, C12Ce and C14Ce exhibited 8- to 12-fold enhanced antimicrobial activity over the parent peptide. In contrast, C18Ce showed reduced antimicrobial activity due to heightened steric hindrance and overly stable assemblies resisting dissociation. The hydrophobic modification not only enhanced the antibacterial activity but also increased their cytotoxicity. Mid-chain derivatives (C8Ce–C14Ce) achieved a higher selectivity index (SI = 5.35–10.33) compared to shorter or longer chains (SI = 0.9–3.73) and the parent peptide (SI = 5.16), highlighting the importance of balancing assembly stability, antimicrobial potency, and toxicity in supramolecular AMP design.

Biofilms are composed of microbial aggregates and their secreted extracellular polymeric substances (EPS). The special structure and composition of biofilms hinder the penetration efficiency of drugs and reduce the therapeutic effect of antibiotics.¹⁶⁴ AMPs are promising candidates for the prevention and treatment of biofilm-associated infections.¹⁸ For example, Mou et al. developed a series of nonapeptides based on either WWW or WW as an assembly-driving and bacterial-targeting motif. The peptide K6 (WWKKWKKWW) can form micelle-like structures via cation–π interactions and hydrophobic interactions.¹⁵³ Compared to peptide monomers without antibacterial activity, the nanostructured ones can efficiently eradicate the majority of extracellular carbohydrates, proteins and nucleic acids, whereas gentamicin had little impact on the biofilm (Fig. 11d). Although the micelles and gentamicin exhibited comparable MICs against planktonic P. aeruginosa–S. aureus co-cultures, the micelles demonstrated superior biofilm-dispersing activity. They further established a catheter-associated biofilm infection model on the dorsal skin of nude mice, demonstrating that the skin tissue in the peptide K6 treatment group recovered to a condition comparable to that of the uninfected control group. In a separate study, Wang and colleagues reported the self-assembly of a cecropin A-derived peptide CADP-10 (Bip-FFKWKLFKK) into supramolecular nanofibers in buffer solution.¹⁶⁵ Compared to the cationic fragment of cecropin A (CADP-7, KWKLFKK), CADP-10 exhibited significant inhibitory effects on the growth of MRSA and multidrug-resistant E. coli (MRE), whereas CADP-7 showed no antibacterial activity. Further investigations confirmed that CADP-10 effectively eradicated bacterial biofilms and penetrated the biofilm matrix to kill the encapsulated MRSA and MRE. The implantation of nanofibers into rabbit tibial defect models in vivo demonstrated that CADP-10 significantly enhances bone regeneration without inducing coagulation toxicity or inflammatory responses, indicating excellent biocompatibility.

4.2. Supramolecular nanofiber network as a bacterial trapper

As a natural cationic AMP secreted by Paneth cells, HD6 has little direct antimicrobial activity but can protect the intestines from pathogenic invasion. Its principal mechanism of action is the capability of HD6 to self-assemble into nanonetworks composed of higher-order oligomers, thereby capturing pathogens and preventing their invasion of host cells.^16,154,166 Inspired by the unique antimicrobial mechanism of HD6, researchers have conducted several studies using biomimetic strategies to construct supramolecular peptide nanofilaments and hydrogels that mimic the antimicrobial actions of HD6.^167,168

For example, Wang et al. designed an HD6 mimetic peptide (HDMP), bis-pyrene-KLVFF-RLYLRIGRR, to emulate the action mechanism of HD6 in preventing bacterial invasion of host cells (Fig. 12a).¹³⁴ This peptide comprises three distinct domains: the targeting peptide RLYLRIGRR, which specifically recognizes lipoteichoic acid (LTA), a unique component on the cell wall of Gram-positive bacteria; the KLVFF sequence, which serves as a β-sheet-forming peptide skeleton; and aromatic bis-pyrene (BP), facilitating self-assembly and enabling fluorescence monitoring of HDMP distribution in vivo. HDMP can self-assemble into nanoparticles that specifically bind to the bacterial cell walls via ligand–receptor interactions, and subsequently form a nanofiber network in situ to ensnare bacteria. They further demonstrated that intravenously administered HDMP nanoparticles preferentially accumulated at the bacterial infection site and exhibited strong binding to bacteria, indicating the effective targeting capability of HDMP in vivo. In a murine MRSA bacteremia model, treatment with HDMP nanoparticles at 5 mg kg⁻¹ resulted in 100% survival, outperforming vancomycin with 83.3% survival at the same dose. Based on a similar concept, the Xu group developed a “trap but not kill” strategy by de novo design of a self-assembling peptide NapFF-GG-SSGGGGSSGGGGH-OH (N-K10) that contains a bacteria-binding domain, a linker, and a self-assembly motif from C- to N-terminus.¹⁴⁷ The peptide sequence SSGGGGSSGGGGH derived from human cytokeratin 10 (K10) is capable of binding to aggregation clumping factor B of S. aureus. The peptide nanofibers specifically bind to the surface proteins of bacteria to selectively capture and trap the bacteria and aggregate into clusters.

Fig. 12 Supramolecular AMPs as a microbial trapper. (a) The molecular structure and TEM images of an HD6-mimetic peptide. Its assembly undergoes a morphological transformation upon exposure to LTA, thereby enhancing bacterial capture. Reproduced with permission.¹³⁴ Copyright 2020 American Association for the Advancement of Science. (b) General sequence and alanine scanning of β-hairpin peptides and their proposed mechanism for bacterial capture. Reproduced with permission.¹⁵⁵ Copyright 2023 Wiley. (c) Schematic illustration of the molecular structure of RFQF4, demonstrating antibacterial trap-and-kill activity and immune modulation for the treatment of bacterial infections. Reproduced with permission.¹⁵⁶ Copyright 2024 American Chemical Society.

On the other hand, Rachel Ee and her colleagues have developed a set of β-hairpin AMPs, including BTT1-3A (LKLKLKLTAKLKLKL-NH₂) and BTT2-4A (LKLKLKVDPPAKLKLKL-NH₂).¹⁶⁹ These AMPs spontaneously formed peptide nanonets in the presence of LTA and lipopolysaccharide (LPS) in Gram-positive and Gram-negative bacteria, demonstrating the dual functionality of capturing and killing bacteria (Fig. 12b).¹⁵⁵ The bacteria-responsive self-assembled peptide exhibited outstanding antibacterial properties, biocompatibility, and resistance to protease hydrolysis. In another similar work, Shan et al. designed a pH-triggered self-assembling β-hairpin peptide WVHHWVHHWVHHpGHHVVHHVVHHVV-NH₂ with dual functions of antibacterial activity and entrapment.¹⁷⁰ Under acidic conditions, the peptide self-assembled into nanoparticles that exhibited potent antibacterial effects. As the pH increased, these nanoparticles gradually transformed into nanofibers, which led to effective bacterial trapping capability. In one of their recent studies, they further designed a multifunctional biomimetic peptide nanonet RFQF4 ((FQFG)₄-SGS-RKVRGPP) with antibacterial trap-and-kill activity and mild immunomodulation (Fig. 12c).¹⁵⁶ The nanofibrils of RFQF4 demonstrated both bacterial capture and bactericidal activity in vitro and in vivo. Their mechanism of action primarily involves destabilizing membrane structures, dissipating the proton motive force, and causing various metabolic disturbances. Moreover, RFQF4 enhanced the antibacterial activity of macrophages by promoting the phagocytosis of E. coli and shifting macrophages toward an anti-inflammatory M2 phenotype.

Furthermore, β-lactam antibiotics are a broad class of β-lactam-containing antimicrobial agents, and their distinctive β-lactam ring is crucial for their antibacterial activity.¹⁷¹ However, bacteria could secrete β-lactamase (Bla) to hydrolyze β-lactam antibiotics, leading to the development of MDR. To address this resistance mechanism, EISA has emerged as an effective strategy. By exploiting the catalytic activity of β-lactamase, EISA facilitates the targeted assembly and formation of bioactive nanostructures at the infection site. Hu et al. designed a Bla-responsive peptide (BLAP) that specifically recognizes the Bla enzyme secreted by MRSA and subsequently undergoes in situ assembly on the bacterial surface to form nanofibers.¹⁷² After incubation with BLAP, the nanofibers formed a supramolecular trapping network that effectively captured MRSA, inducing bacterial aggregation and coagulation. They further demonstrated that BLAP exhibited no cytotoxic effects on 293T or THP-1 cells. In addition, BLAP treatment significantly inhibited MRSA invasion into both 293T and THP-1 cells.

4.3. Supramolecular assemblies for antimicrobial delivery

Recently, supramolecular materials have been identified as one of the most important drug delivery systems that can enhance the efficacy of pharmaceuticals in clinical settings by precisely delivering appropriate doses of therapeutic agents to targeted sites and achieving controlled release.^173–175 In the case of supramolecular AMPs, a series of antibacterial agents (i.e., antibiotics, AMPs, metal particles) could be loaded into the nanostructures to yield diverse stimuli-responsive peptide assemblies, which offer an innovative approach to demonstrate the versatile potential of antimicrobial peptides as drug delivery systems to combat bacterial infections.

Supramolecular peptide hydrogels can form highly hydrated, dynamic 3D networks with excellent biocompatibility and biodegradability. As ideal carriers for drug delivery, they can efficiently encapsulate antibacterial agents within the gel matrix and enable sustained release of antibacterial drugs at infection sites. For instance, Yuan et al. designed an antibacterial nanofiber network (ACFP) possessing hemostatic properties through the co-assembly of an AMP (CRCICGRGICRCICGRGI-NH₂) with a RADA-rich hemostatic gel.¹⁷⁶ MD simulations revealed rapid formation and merging of peptide clusters into stable fibrous networks. Analysis of structural parameters and free energy landscapes confirmed the formation of a biomimetic dynamic hydrogel, primarily driven by electrostatic interactions and hydrophobic interactions. The peptide hydrogels exhibited negligible cytotoxicity toward human vascular endothelial cells (HUVECs). Moreover, no signs of allergic reactions were observed following topical application on the dorsal skin of lactating mice for three consecutive days, indicating minimal immunogenicity. The co-assembled biomimetic nanonets possess antibacterial, anti-inflammatory, and repair-promoting properties, showing effectiveness in various chronic wound mouse models. In another intriguing work, the AMP Jelleine-I (J-1) was originally isolated from honey bee royal jelly and it consisted of the short sequence PFKLSLHL-NH₂. The AMP J-1 can form hydrogels in sodium adenosine diphosphate (ADP) solution, 8Br-cyclic adenosine monophosphate (8Br-cAMP) solution, and phosphate buffered solution (PBS) without any chemical cross-linking agents.^157,177,178 In buffered solution, J-1 predominantly adopts a β-sheet conformation. When metal ions shield their charged groups, the peptides self-assemble into nanofibers via hydrogen bonding and hydrophobic interactions, which then crosslink to form hydrogels with potential applications in hemostasis and wound healing. In these systems, the AMP J-1 acts as both the active compound and the self-assembling monomer, realizing self-formulating and self-delivery.

The unique pathological markers of the bacterial infection microenvironment (e.g., acidic pH, bacterial-specific components, and overexpressed enzymes) provide crucial biological guidance for the rational design of novel stimuli-responsive antibacterial materials.^172,179 Bacterial infections often induce an acidic microenvironment due to factors such as bacterial metabolism, host immune responses, hypoxia, and tissue necrosis. Recent studies have demonstrated various strategies for designing self-assembled peptide hydrogels with tunable pH responsiveness for antibacterial applications. For example, Wang et al. engineered an octapeptide (IKFQFHFD) that can self-assemble into nanofibers at neutral pH and disassemble under acidic conditions, thereby exhibiting pH-switchable antibacterial activity.¹⁵⁸ Moreover, when these nanofibers are loaded with cypate and proline, the IKFQFHFD hydrogel degrades under acidic pH conditions, enabling on-demand release of cypate within the pathological microenvironment of infected chronic wounds. The released cypate disrupts the EPS matrix, enhancing biofilm permeability, thereby improving the hydrogel's efficiency in biofilm removal and facilitating controlled drug release at the infection site. Furthermore, hydrogels can encapsulate or co-assemble with drugs that exhibit low in vivo stability and poor water solubility, thereby enabling sustained release at the infection site. In addition, these hydrogels can work synergistically with peptides to enhance drug pharmacokinetics and pharmacodynamics.¹⁴² For instance, Rao and his colleagues designed an array of pH-responsive self-assembling peptides.¹³⁵ At pH 7.4, AMP L5 (Ac-KPVFQFLFHE-NH₂) self-assembled into a uniformly entangled 3D porous network with an average pore diameter of 5.6 μm, as revealed by cryo-TEM. The formed hydrogel exhibited a combination of β-sheet and α-helix conformations and demonstrated excellent biocompatibility toward HaCaT cells and mouse red blood cells. In contrast, AMP L5 underwent dramatic structural changes at pH 5.5 and predominantly adopted a random coil conformation, triggering disassembly and the release of broad-spectrum antimicrobial activity. RNA sequencing analysis revealed that the L5@LysSYL hydrogel can suppress membrane- and cell wall-associated genes in MRSA, leading to membrane disruption, inhibition of cross-wall formation, and delayed cell separation. Furthermore, encapsulating endolysin LysSYL, which exhibits promising antistaphylococcal activity but instability under acidic conditions, produced a supramolecular L5@LysSYL hydrogel with sustained release properties that improved its stability and bioavailability (Fig. 13a). In another work, Li et al. developed a co-assembling system containing a sparingly soluble antibiotic (levofloxacin; Lev) and the PA Dex-SA-RGD (Dex refers to dexamethasone and SA refers to succinic anhydride).¹⁴⁸ The co-assembling system can assemble into uniform nanotubes and form supramolecular hydrogels under physiological conditions. The hydrogel first released Lev at the infection site, while Dex-SA-RGD escaped from the supramolecular hydrogel due to matrix erosion and then served as a prodrug to slowly release active Dex via the hydrolytic pathway.

Fig. 13 Supramolecular AMP mediated antimicrobial delivery. (a) Schematic illustration of a pH-responsive L5@LysSYL hydrogel that releases LysSYL at acidic infection sites for wound treatment. Reproduced with permission.¹³⁵ Copyright 2024 Wiley. (b) Design principles underlying CPCs and enzyme-triggered morphological transitions facilitate preferential accumulation of nanomaterials at infection sites and targeted exposure of AMPs, exhibiting efficient antibacterial efficacy. Reproduced with permission.¹³⁶ Copyright 2017 Wiley. (c) Molecular design of PAs modified with aldehyde groups for catalytic AgNP formation. Reproduced with permission.¹⁸⁰ Copyright 2016 American Chemical Society.

Separately, Wang and his colleagues presented a novel biointerface design using a modular self-assembly strategy with stimuli-responsive properties for tissue engineering.¹⁸¹ The surface was modified with a three-layer structure, incorporating a cell-adhesive peptide (RGD), a responsive peptide that cleaves in bacterial infection sites, and an antifouling layer made of hexaethylene glycol (HEG). The peptides, which are sensitive to bacterial enzymes such as gelatinase and coagulase, can undergo cleavage upon infection, exposing the HEG layer that inhibits biofilm formation. In vitro and in vivo experiments showed significant improvements in cell adhesion, biofilm inhibition, and antibacterial efficacy. Subsequently, they synthesized a transformable chitosan-peptide conjugate (CPC), consisting of three components: a chitosan backbone, an enzyme-cleavable peptide GPLG-VRGC with a PEG terminus, and an AMP KLAK (CGGGKLAKLAKKLAKLAK).¹³⁶ Upon exposure to gelatinase secreted by bacteria at the infection site, the peptide is cleaved, causing the CPC to transition from nanoparticles into fibrous structures. This transformation enhanced the accumulation and retention in infected tissues and exposed the α-helical KLAK peptide, which interacts electrostatically with bacterial membranes, leading to membrane disruption and bacterial death (Fig. 13b). They further validated in a mouse infection model that the morphological transformation of CPC markedly improved its accumulation at the infection site, leading to an extended retention time with a half-life (τ_1/2) of up to 4 days. Recently, Li and co-workers designed an enzyme-responsive peptide SAP-MP196-G-1 (DDDEEKRWRWRWGPLGVRGD), consisting of a hydroxyapatite-adsorbing motif DDDEEK, an antibacterial motif RWRWRW, a bacterial enzyme-responding motif GPLGV, and a cell adhesion motif RGD.¹⁸² The SAP-MP196-G-1 molecule can self-assemble into nanoparticles at the beginning, tightly adsorb to the HA surface and subsequently form a film via the peptide sequence RGD. Upon adsorption onto HA surfaces, this biointerface demonstrated dual-stage antibacterial action: initially resisting bacterial adhesion through super-hydrophilicity, followed by exposing the antibacterial peptide RWRWRW after cleavage of enzyme-responsive linker GPLGV by S. aureus secreted gelatinase.

Metals have been employed as antibacterial agents in the early centuries. The use of metal–peptide coordination chemistry to create well-defined nanostructures represents another effective strategy for enhancing the therapeutic potential of metal nanoparticles.^159,183 The Wang group engineered gold nanoparticles (AuNPs) with functional peptide P1 (CLVFFAEDPLGVRGRVRSAPSSS) via Au–S bonds that can self-assemble into nanoparticles.¹⁸⁴ This peptide integrates three modules: β-sheet-forming LVFFAED for self-assembly, collagenase IV-cleavable PLGVRG linker, and S. aureus-targeting ligand RVRSAPSSS, enabling enzymatic activation and pathogen-specific accumulation. Upon intravenous administration, AuNPs@P1 nanoparticles targeted bacterial surfaces through RVRSAPSSS ligands. Bacterial collagenase IV then cleaved the PLGVRG linker, which can trigger AuNP aggregation and induce localized surface plasmon resonance (LSPR) redshift for amplified photoacoustic signals. The assembly-induced retention (AIR) effect enhanced localized accumulation, significantly improving early infection detection sensitivity. In a similar work, Lai et al. grafted ultrashort peptides into gold nanoparticles through electrostatic interactions and Au–S bonds. These dipeptide (CR)-Au nanoparticles demonstrated potent bactericidal activity and specificity against S. aureus by interacting with bacterial membranes.¹⁸⁵

The Stupp group designed PA1 [Ac-E(CH₂CHO)E₃A₃V₃K(C₁₆)-NH₂] nanofibers with aldehyde functionalization, facilitating the formation of uniformly sized and spatially organized silver nanoparticles (AgNPs) on PA fibers in aqueous solution without the need for additional reducing agents (Fig. 13c).¹⁸⁰ The metallized nanofibers exhibited an antibacterial effect against E. coli comparable to that of AgNO₃ solution, while demonstrating reduced cytotoxicity toward murine C2C12 myoblasts compared to AgNO₃ alone. Similarly, Reithofer et al. designed a self-assembling short peptide (Ac-LIVAGK-NH₂) capable of forming a composite peptide hydrogel (Ag-Ac-LIVAGK-NH₂) in aqueous buffers.¹⁸⁶ This short peptide demonstrated antibacterial efficacy comparable to tetracycline over a short duration and outstanding antibacterial performance within 24 hours. In addition, Yan and co-workers screened four metallized hydrogels that were formed through coordination interactions between Fmoc-amino acids and silver.¹⁸⁷ These hydrogels efficiently prevented the self-aggregation of AgNPs, enhancing the stability of AgNPs and endowing the metallized hydrogels with adjustable mechanical properties. The hydrogels can control and sustain the localized release of antibacterial amino acids along with AgNPs. Therefore, employing a supramolecular peptide assembly strategy to engineer well-defined nanostructures holds promise for enhancing the antibacterial efficacy and biocompatibility of both antibiotics and metal nanoparticles. This approach can effectively lower drug dosage and toxicity, and increase bioavailability.

5. Conclusions and perspectives

Supramolecular assembly of AMPs into well-defined nanostructures displays a great potential to address the facing limitations of AMPs in stability, toxicity, and pharmacokinetics. Compared with traditional antibacterial materials, supramolecular AMPs integrate the advantages of tunable structure, nanoformulation, multimodal bactericidal action, and dynamic responsiveness. By carefully tailoring the molecular design of AMPs, one can precisely regulate self-assembly behavior and functional properties to create a series of nanomaterials for specific applications. The well-defined assemblies possess enhanced germicidal capacity, improved serum stability, increased host compatibility and prolonged circulation, thereby improving pharmacokinetics and amplifying the therapeutic outcomes. Supramolecular AMPs can also effectively eradicate biofilms and resistant pathogens through multiple mechanisms, including membrane disruption, intracellular targeting, immune modulation, or their synergistic combination. Furthermore, biomimetic capturing strategies can be employed to prevent bacterial infections by mimicking natural immune defense systems with nanoassembly networks. In addition, noncovalent interactions endow supramolecular AMPs with intrinsic dynamic and stimulus-responsive properties, facilitating controlled disassembly in response to physiological stimuli and localized release of active antimicrobial agents. These multidimensional advantages distinguish supramolecular AMPs from classic antibiotics and antibiotic nanostructures, serving as an emerging platform for addressing the challenges posed by evolving resistance paradigms. In this review, we have summarized recent advances in supramolecular peptides as antibacterial materials, focusing on molecular design, self-assembly and potential applications. Through the synergism of multiple noncovalent interactions (i.e., hydrogen bonding, hydrophobic effects, π–π stacking, and electrostatic interactions), precision assembly of peptides can create various nanoarchitectures, which significantly increases optimized biostability, targeted antimicrobial activity as well as the antibiotic efficacy. With advanced structural design, pathogen-localized self-assembly yields in situ a nanofibrous network via interfacial interactions, and enables real-time microbial entrapment. The supramolecular engineered hydrogels with hierarchically ordered structures also emerge as novel platforms for spatiotemporally controlled drug delivery.

Although remarkable progress has been made in the development of supramolecular AMPs, significant challenges persist in translating these innovations into clinical practice. Firstly, a major challenge lies in how to rationally design or modify AMPs to make them self-assembling without compromising their antimicrobial efficacy. By enabling the swift exploration of chemical space, AI offers a powerful approach for the rapid screening of extensive peptide candidates and the precise prediction of their antimicrobial potential and self-assembly behaviors, which may provide an access to address this trade-off. Second, due to the significant cytotoxicity of many AMPs, it remains as a significant challenge to achieve broad-spectrum antibacterial activity and selectively eliminate pathogens without harming healthy cells. A potential strategy may be incorporating advanced targeting strategies or in situ responsiveness capabilities, according to the differences between the bacterial microenvironment and normal tissues. This approach would enable self-assembled AMPs to preferentially exert their effects at infection sites, thereby minimizing damage to normal cells. Third, the inherently dynamic nature of supramolecular assembly poses a challenge for batch-to-batch reproducibility, since different assembly pathways may yield supramolecular materials with varying microstructures and properties. Possible strategies may include regulating the self-assembly behaviors through rational molecular design and minimizing the influences of self-assembly pathways and kinetics to yield thermodynamically stable supramolecular nanostructures. Fourth, when supramolecular assemblies enter the body, peptides are susceptible to degradation in complex physiological environments, which may result in uncontrolled disassembly and compromise structural integrity and therapeutic performance. A promising approach involves the deliberate integration of non-natural amino acids, cyclization, or the incorporation of covalent and non-covalent hybrids into the supramolecular system. Such modifications can enhance the chemical stability of nanostructures and lead to prolonged therapeutic efficacy. Fifth, scaling production while maintaining precise control over peptide nanostructures remains economically and technically challenging, creating barriers to widespread clinical adoption. On the one hand, advanced synthetic technologies (e.g. α-amino acid N-carboxyanhydrides, microbial fermentation, and automated flow chemistry) serve as potential methods to reduce the consumption of solvents/reagents, shorten the cycle time, and increase the overall yield of peptides. On the other hand, clinical translation of peptide assemblies requires standardized operating procedures (SOP) for supramolecular AMP production, encompassing synthesis, self-assembly and sterilization. Strictly controlling the process parameters and reasonably designing supramolecular short peptide sequences reduce the difficulties of synthesis and industrial scale-up. Finally, although the great potential of supramolecular AMPs has been confirmed in preclinical studies, challenges still exist in translating these supramolecular materials into clinical applications. We believe that the continuous improvements of programmable self-assembling AMPs and supramolecular nanostructure engineering will make supramolecular AMPs promising candidates to combat bacterial resistance.

Author contributions

The manuscript was written through the contributions of all authors. All authors have approved the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (22475140, 52273136), the National Key R&D Program of China (2024YFA1212300), and the Sichuan Science and Technology Program (2023YFH00711).

Notes and references

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