Salmonella is a pathogenic bacterium isolated from pig intestines during the cholera epidemic of 1885 1. Salmonella is a gram-negative bacterium that belongs to the family Enterobacteriaceae and is an acidophilic facultative anaerobic bacterium that can rely on systemic flagellar motility 2. Infection with Salmonella typically presents with nonspecific clinical symptoms 3. To date, more than 2600 serotypes ofSince their discovery in the twentieth century, antibiotics have been the mainstay of treatment for salmonellosis. For example, Conventional antibiotics including chloramphenicol (inhibiting peptide chain elongation to block protein synthesis) 11; quinolone antibiotics (levofloxacin, ciprofloxacin) interfere with bacterial growth and reproduction by preventing DNA replication and RNA transcription 12; thirdgeneration cephalosporins inhibit cell wall synthesis and thus exert an inhibitory effect 13; and different antibiotics have shown good therapeutic effects on Salmonella 141516. However, the widespread and often injudicious use of antibiotics in human and veterinary medicine has led to a dramatic increase in antimicrobial resistance (AMR) 17. Salmonella strains undergo genetic mutations, rendering them resistant to antibiotics to which they were previously susceptible, leading to bacterial populations with increased overall resistance 18. Aslam et al. reported a high prevalence of antimicrobial resistance among Salmonella isolates recovered from retail meats, with multidrug resistance being frequently observed. Resistance was particularly common to several clinically and veterinary important antimicrobials, and distinct resistance gene profiles were associated with specific Salmonella lineages, indicating that foodborne Salmonella constitutes a significant reservoir of antimicrobial resistance 19.Beyond antimicrobial resistance, antibiotic tolerance has increasingly been recognized as a distinct and clinically relevant contributor to treatment failure in Salmonella infections 20. Tolerance is mainly manifested as the prolonged survival time of bacteria under antibiotic exposure 21. This physiological state markedly diminishes the efficacy of many conventional antibiotics whose bactericidal activity depends on active cellular processes, including cell wall synthesis, DNA replication, and protein translation. As a consequence, intracellular Salmonella can survive prolonged antibiotic treatment, contributing to delayed clearance, relapse, and chronic infection. Recent studies have highlighted antibiotic tolerance as a major physiological consequence of Salmonella's adaptation to the intracellular niche and a key determinant of treatment failure despite apparent in vitro susceptibility 22,23. This phenomenon poses a serious threat to global public health and could cause approximately 10 million deaths annually by 2050 if it is not effectively controlled 24,25.In response to the AMR crisis, biological therapies, including bacteriophages (phages) 26, probiotics 27, and vaccines 28, have emerged as promising alternatives for the treatment and control of salmonellosis. These approaches offer the potential for high efficacy with minimal side effects compared to conventional antibiotics. Generally, phages function by directly destroying the bacterial cell structure; probiotics modulate the intestinal environment, compete with pathogens, and stimulate host immunity; and vaccines induce specific, long-lasting immune protection.The "promise" of these biotherapies extends beyond their direct antimicrobial effects. Their potential for more targeted action. This review aims to compile the most up-to-date information on these biotherapeutic modalities for zoonotic salmonellosis, encompassing their methods of application, underlying mechanisms of action, functional benefits, and progress in clinical research. Furthermore, it seeks to provide a theoretical foundation for future research directions and facilitate the establishment of safer, more effective Salmonella control systems.Bacteriophages are the most ubiquitous biological organisms in nature. They are viruses that can infect bacteria 29. Compared with broad-spectrum antibiotics, phages have high specificity and do not damage coexisting bacterial flora; they have the advantages of wide distribution, simple isolation, a short development cycle, low cost, relatively strong environmental stability under specific conditions, and low toxicity and side effects 30,31. Bacteriophages are divided into lytic phages (which attach to host cells and replicate by releasing new phages) and temperate phages (which integrate their genome into the host cell and replicate) 32. (Figure 1) For therapeutic applications, strictly lytic phages are overwhelmingly preferred due to significant safety concerns associated with temperate phages. Temperate phages carry the inherent risk of horizontal gene transfer, potentially transferring virulence factors or antibiotic resistance genes from the phage genome or the host bacterium to other bacteria 33. Furthermore, their lytic conversion is unpredictable and dependent on environmental cues, which compromises treatment reliability. Consequently, lytic phages, which offer immediate and controlled bactericidal effects without the risk of genetic transfer, are the exclusive choice for current clinical applications, unless lysogenic variants are genetically modified to irreversibly disable their integration capabilities. This fundamental safety consideration dictates phage selection criteria and informs strategies for phage engineering 29. Extensive research has demonstrated the efficacy of phage therapy through its lytic action against pathogenic bacteria, effectively suppressing their growth and proliferation 34. The bactericidal strategies employed by phages are diverse, as summarized in Table 1. Robert et al. reported a significant decrease in light intensity within 1 minute after spraying the lytic phages Eϕ151 or Tϕ7 onto the skin of chickens infected with bioluminescent S. Enteritidis P125109 or S. Typhimurium 4/74, respectively 35, demonstrating the lytic activity of the phages against Salmonella.Similar effective lysis by the phage was observed in milk or eggs contaminated with Salmonella 363738. Phages can decrease the in vivo colonization of Salmonella.Mengzhe et al. reported that administering phage STP4-a to S. Typhimurium ATCC14028-infected chickens for 7 consecutive days resulted in a reduction in bacterial counts in the feces, which could be attributed to the ability of the phage to catch and kill bacteria in the intestine, subsequently preventing bacterial colonization 39. MiJin et al. reported a decrease in the expression of pro-inflammatory cytokines such as IL-6, IFN-γ and TNF-α and an increase in the expression of anti-inflammatory cytokines such as IL-4 and HSP27 after Salmonella-infected laying hens were treated with the BF2165 phage. This outcome was attributed to the ability of the phage to inhibit the colonization of Salmonella, thereby reducing the inflammatory burden on tissues caused by Salmonella 40. These findings demonstrate that phage therapy not only directly eliminates Salmonella but also modulates host immune responses by rebalancing pro-and anti-inflammatory cytokine networks.While these studies highlight the potential of single phage interventions, the inherent ability of bacteria to develop resistance to individual phages is a recognized challenge. This observation of emerging phage resistance, even if overcome by other specific phages, implicitly drives the field towards more robust strategies, such as phage cocktails and engineered phages, designed to preempt or manage this evolutionary pressure.To address the limitations of single phage therapy, particularly their narrow host range and the potential for rapid emergence of phage-resistant bacterial mutants, phage cocktails have gained prominence. Phage cocktails are formulations containing multiple distinct phages, often selected for their complementary lytic spectra or different mechanisms of action, thereby broadening the overall efficacy and significantly reducing the likelihood of resistance development 33. Yadav et al. orally administered a phage cocktail (phage hM1, hHC/T or HC-M1) to a group of albino mice infected with S. Typhimurium for 7 days. The results revealed that not only did the mice survive without any deaths but also that the bacteria were completely eradicated and remained absent for up to 2 months. In contrast, the untreated control group presented a 100% mortality rate. These findings indicate that phage cocktail treatment provides a high level of antimicrobial efficacy and has a prolonged effect 41. In a separate study, a cocktail comprising five distinct phages (phages A7, A8, B3, A4 and A5) was evaluated on chicken meat contaminated with various Salmonella serotypes, resulting in a 1.4 Log10 reduction in bacterial load compared with the control 42.The therapeutic efficacy of bacteriophages can be significantly hampered by their susceptibility to harsh environmental conditions, such as acidic pH in the stomach, high temperatures during feed processing, or the presence of digestive enzymes 43. To overcome these challenges and enhance phage stability, delivery, and lytic activity, microencapsulation techniques have been developed. Microencapsulation involves entrapping phages within a protective matrix, which can shield them from detrimental conditions and facilitate their targeted release at the site of infection 44. In a recent study, supplementation of the starting diet with L100-encapsulated phage as a feed additive during rearing significantly reduced the incidence of flock contamination with S. Enteritidis. Moreover, complete eradication of this pathogen from the environment was achieved, accompanied by a reduction in Salmonella colonization and excretion at the end of the rearing period 45. Parallel research confirms these findings, showing that microencapsulated phage T156 exhibits superior stability and enhanced lytic activity against drug-resistant Salmonella strains 46.While phages are often considered alternatives to antibiotics, emerging evidence suggests that combining phages with conventional antibiotics can lead to synergistic effects, producing superior therapeutic outcomes compared to either agent used alonea strategy known as Phage-Antibiotic Synergy (PAS) 47. 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Enteritidis compared to the antibiotics The enhanced activity was attributed to in bacterial which cell lysis by to lytic the of phages, and thereby phage This suggests that is not an additive effect but a on specific biological for more designed findings the potential of to enhance treatment overcome resistance, and potentially or the of antibiotics. However, it be that these effects are and under conditions, such as antibiotics are used at bactericidal that host replication to the phage the microencapsulated phage exhibits superior inhibitory effects against S. Enteritidis with enhanced stability and in of microencapsulated phage to chickens infected with S. targeted of the phage to the the colonization it lytic activity and the efficacy of phage Phage Enteritidis Phage Phage Phage Phage in vivo and in vitro demonstrated the enhanced efficacy of the phage cocktail of phages and against S. Enteritidis thereby significantly the emergence of phage-resistant Salmonella Typhimurium S. S. 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Ma et al. (Wed,) studied this question.