Due to the evolution of microbial resistance, the current generation of antibiotics cannot keep abreast with the development of new strains [1]. Unlike traditional antibiotics that inhibit microbial metabolism, nanomaterials achieve antibacterial effects through various mechanisms, such as biofilm dissolution, oxidative stress reactions, regulation of protein and DNA replication, and physiological damage [2]. Thus, nanomaterial-based antimicrobial agents have the potential to replace antibiotics.

Metal oxide nanoparticles are extensively used in biomedicine as antioxidants, antimicrobials, and anticancer agents due to their ease of preparation and high biocompatibility [3], [4]. Multiple physical, chemical, and biological techniques have been used to synthesize nanoparticles. However, these physical methods consume substantial amounts of energy and are costly. The synthesis of nanoparticles adversely affects both organisms and the environment because of the use of toxic chemicals. Using biological resources, such as plants and microorganisms, as the basis for chemical synthesis is cost-effective and harmless [5]. This approach provides an appropriate method for synthesizing nanoparticles. Plants are particularly advantageous because the reduction process is mediated by bioactive substances present in plants [6]. Therefore, the biotechnological synthesis of nanoparticles using plants is considered a green pathway.

Artemisinin is a sesquiterpene lactone peroxide isolated from Artemisia annua L. As a secondary metabolite, artemisinin has the potential to produce nanoparticles. Its primary mode of action involves the disruption of membrane-mitochondrial function. Apart from treating malaria, it also exhibits antibacterial effects against bacteria, such as Alternaria tabacum, Escherichia coli, and Staphylococcus aureus [7], [8]. However, artemisinin has several drawbacks; its short half-life and low solubility limit its application [9]. Josias [10] proposed that the combination of artemisinin with various nanoparticle systems could enhance its stability and bioavailability.

Zinc-based nanoparticles have been extensively studied in the field of metallic nanoparticles. There are several ways in which zinc nanoparticles enhance antibacterial activity against drug-resistant bacteria:1) inducing intracellular antibacterial effects; 2) enhancing drug solubility; 3) generating reactive oxygen species (ROS); and 4) disrupting biofilms [11]. Double-sided nano-ZnO prepared by He et al. [12] exhibits excellent antibacterial effects and effectively suppresses the inflammatory response induced by S. aureus. Jiang et al. [13] investigated the potential antibacterial mechanisms of ZnO nanoparticles against E. coli. Their findings revealed that the disruption membrane integrity and generation of ROS play crucial roles in the antibacterial activity of ZnO nanoparticles. However, when zinc nanoparticles enter the body through routes, such as oral ingestion, inhalation, or skin penetration, they may cause toxicity, hypersensitivity, or mutagenicity [14], [15].

When new antibiotics are developed, bacterial resistance can emerge within a relatively short period. Given the substantial body of research documenting their excellent antibacterial properties, metal nanoparticle antimicrobials could potentially serve as a solution to antibiotic resistance. Furthermore, we believe that the combination of artemisinin and zinc nanoparticles can mitigate the toxicity of nanomaterials and enhance the bioavailability of artemisinin.

This study aimed to synthesize an orally bioactive nanoscale antimicrobial agent with enhanced bactericidal activity using a green synthetic strategy. We evaluated its effectiveness against Salmonella and E. coli. The physicochemical properties of the prepared nanoparticles were characterized through a series of analyses. Biofilm experiments were conducted to explore potential mechanisms of action. The safety and therapeutic effects of the nanoparticles were assessed in mice.