The abuse of traditional antibiotics has caused a series of health problems including antimicrobial resistance, which threatens human health. Therefore, searching for broad sources of antimicrobial agents and developing multidimensional strategies to combat bacterial infections are urgent. Here, we reported two natural selfassembling modes between berberine (BBR) and flavonoid glycosides: nanoparticles (NPs) and nanofibers (NFs), which were both mainly governed by electrostatic and hydrophobic interactions. These two nanostructures exhibited different antibacterial properties from BBR. NPs showed significantly enhanced bacteriostatic activity, whereas NFs displayed a much weaker effect than BBR. The distinguishing properties can be attributed to the different spatial configurations and self-assembly processes of NPs and NFs. Flavonoid glycosides and BBR first formed a one-dimensional complex unit and subsequently self-assembled into three-dimensional nanostructures. With the hydrophilic glucuronic acid toward the outside, NPs exhibited stronger affinity to bacteria, thereby inducing the collapse of the bacteria population and the decrease in biofilm. In addition, in vitro hemolysis tests, cytotoxicity tests, and in vivo zebrafish toxicity evaluation showed that the obtained self-assemblies had good biocompatibility. This supramolecular self-assembly strategy can be applied to construct other nanoscale antibacterial drugs and thus provides weapons for the development of self-delivering drugs in bacterial infection treatment.

S. aureus is resistant to various first-line antibiotics, and seeking multifarious strategies aimed at effective control of antibiotic-resistant behavior is urgently needed. Here, we report a two-component directed self-assembly mode: the phytochemicals berberine and cinnamic acid can directly self-assemble into nanoparticles (NPs) displaying good bacteriostastic activity. Compared with several first-line antibiotics, the obtained nanostructures have a better inhibitory effect on multidrug-resistant S. aureus (MRSA) and stronger ability for biofilm removal. These qualities are attributed to the fact that organic assemblies can first spontaneously adhere to the surface of the bacteria, infiltrate into the cell, and then lead to converging attack against MRSA; thereafter, multipath bactericidal mechanisms of NPs on MRSA are found by both transcriptomic analysis and quantitative Polymerase Chain Reaction analysis. Moreover, when combined with spectral data and single crystal X-ray diffraction, the NPs’ self-assembly mechanism governed by hydrogen bonds and π–π stacking interactions is clearly elucidated. These non-covalent interactions induce the NPs’ formation of butterfly-like one-dimensional self-assembled units and finally layered three-dimensional spatial configuration. In addition, biocompatibility tests show that the NPs are nonhemolytic with little toxicity in vitro and in vivo. This directed self-assembly mode can offer a new perspective toward the design of biocompatible antimicrobial nanomedicines for clinical translation.

The application of nanotechnology for antimicrobial delivery has capacity to improve antibacterial efficacy. Currently, the usage of various inorganic and organic carriers, such as metal ions, nano-silicon and surfactants, might increase the potential toxicity of nanoparticles and make their clinical transformation more difficult. Herein, a nano-delivery system was constructed by direct self-assembly of antibacterial phytochemicals (berberine and rhein) originated from traditional Chinese medicine Coptis chinensis Franch. and Rheum palmatum L., respectively. Combining X-ray single crystal diffraction, nuclear magnetic resonance and other spectra characterizations, the stacked structure of nanoparticles was profoundly demonstrated. Briefly, rhein acted as the layered backbone and berberine embedded in it. In vitro bacteriostasis experiment showed the minimum bactericidal concentration of nanoparticles was 0.1 μmol/mL, which was lower than that of berberine and rhein. The results of confocal laser scanning microscope, biofilm quantitive assay and scanning electron microscopy indicated that nanoparticles had strong inhibitory effects on Staphylococcus aureus biofilm. More importantly, transmission electron microscopy and mass spectra indicated the further bacteriostatic mechanism of nanoparticles. Meanwhile, the nanoparticles had well biocompatibility and safety. Current study will open up new prospect that the design of self-assemblies between active phytochemicals can be originated from traditional Chinese medicine combination.

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Aristolochic acid (AA) has been reported to cause a series of health problems, including aristolochic acid nephropathy and liver cancer. However, AA-containing herbs are highly safe in combination with berberine (Ber)-containing herbs in traditional medicine, suggesting the possible neutralizing effect of Ber on the toxicity of AA. In the present study, in vivo systematic toxicological experiments performed in zebrafish and mice showed that the supramolecule self-assembly formed by Ber and AA significantly reduced the toxicity of AA and attenuated AA-induced acute kidney injury. Ber and AA can self-assemble into linear heterogenous supramolecules (A–B) via electrostatic attraction and π–π stacking, with the hydrophobic groups outside and the hydrophilic groups inside during the drug combination practice. This self-assembly strategy may block the toxic site of AA and hinder its metabolism. Meanwhile, A–B linear supramolecules did not disrupt the homeostasis of gut microflora as AA did. RNA-sequence analysis, immunostaining, and western blot of the mice kidney also showed that A–B supramolecules almost abolished the acute nephrotoxicity of AA in the activation of the immune system and tumorigenesis-related pathways.