Methicillin‐resistant Staphylococcus aureus (MRSA)‐infected skin wounds have caused a variety of diseases and seriously endanger global public health. Therefore, multidimensional strategies are urgently to find antibacterial dressings to combat bacterial infections. Antibacterial hydrogels are considered potential wound dressing, while their clinical translation is limited due to the unpredictable risks and high costs of carrier excipients. it is found that the natural star antibacterial and anti‐inflammatory phytochemicals baicalin (BA) and sanguinarine (SAN) can directly self‐assemble through non‐covalent bonds such as electrostatic attraction, π–π stacking, and hydrogen bonding to form carrier‐free binary small molecule hydrogel. In addition, BA‐SAN gel exhibited a synergistic inhibitory effect on MRSA. And its plasticity and injectability allowed it to be applied as a wound dressing. Due to the matched physicochemical properties and synergistic therapeutic effects, BA‐SAN gel can inhibit bacterial virulence factors, alleviate wound inflammation, promote wound healing, and has good biocompatibility. The current study not only provided an antibacterial hydrogel with clinical value but also opened up new prospects that carrier‐free hydrogels can be designed and originated from clinically used small‐molecule phytochemicals.

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The carrier-free self-assembly of small molecules opens a new window for the development of nanomaterials. This study is dedicated to developing binary small-molecular self-assemblies derived from phytochemicals in traditional Chinese herbal medicine. Among them, Rhei Radix et Rhizoma and Coptidis Rhizoma are a common pair used in clinics for thousands of years. Here, we found that there were numerous spherical supramolecular nanoparticles (NPs) originated from Rhei Radix et Rhizoma and Coptidis Rhizoma decoction. Ultra-performance liquid chromatography/ tandem mass spectrometry (UPLC-MS/MS) was used to analyze the composition of the supramolecules, and a total of 119 phytochemicals were identified (23 anthraquinones, 31 alkaloids, 24 organic acids, 8 tannins, and other components). Isothermal titration calorimetry (ITC) showed that the interaction between Rhei Radix et Rhizoma and Coptidis Rhizoma was a spontaneous exothermic reaction, indicating that their phytochemicals had the property of self-assembly and interacted to form supramolecules in the decocting process. Furthermore, scanning electron microscopy (SEM), UV, IR, NMR, and ITC were used to verify that rhein and coptisine could self-assemble into nanofibers (Rhe-Cop NFs), while emodin and coptisine could self-assemble into nanoparticles (Emo-Cop NPs). The formation mechanism analysis of the self-assemblies revealed that they were induced by electrostatic attraction, hydrogen bonding, and π−π stacking, forming nanospheres of about 50 nm and nanofibers. The current study not only provides an idea of discovering carrier-free self-assemblies from traditional herbal medicine decoction but also supplies a reference for the design of binary self-assembly of small molecules in the future.

Antibacterial hydrogels have gradually become a powerful weapon to treat bacterially infected wounds and accelerate healing. In this paper, we designed a small-molecule self-healing antibacterial hydrogel containing 100% drug-loaded benzyl 3β-amino-11-oxo-olean-12-en-30-oate (GN-Bn), which was governed by π−π stacking, hydrogen bonding, and van der Waals forces. Due to the carrier-free design concept, the problems of interbatch variability during sample preparation and carrier-related toxicity can be effectively avoided. Moreover, the GN-Bn hydrogel exhibited promising antibacterial activities against multidrugresistant Staphylococcus aureus (MRSA). The minimum inhibitory concentration (MIC) of the GN-Bn hydrogel was 1.5625 nmol/ mL, which was lower than those against clinical agents such as norfloxacin, penicillin, and tetracycline. This is attributed to its unique antibacterial mechanism that aims at killing bacteria or preventing their growth by regulating arginine biosynthesis and metabolism through both transcriptomic (RNA-seq) analysis and quantitative polymerase chain reaction (qPCR) analysis. In addition, the GN-Bn hydrogel can also inhibit proinflammatory cytokines (TNF-α, IL-1β, and IL-6) to promote wound healing. Collectively, the GN-Bn hydrogel elicited dual therapeutic effects on an MRSA-infected full-thickness skin wound model through its antibacterial and anti-inflammatory activities, which is attributed to the fact that the GN-Bn hydrogel has multiple advantages including sufficient mechanical stability, biocompatibility, and unique antibacterial mechanisms, making it significantly accelerate MRSA-infected full-thickness skin wound healing as a wound dressing. In a word, the GN-Bn antibacterial hydrogel dressing with an anti-inflammatory and antibacterial bifunctional material holds great potential in clinical application.

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