Antimicrobial resistance (AMR) is a critical global health concern, responsible for at least 1.27 million deaths in 2019, a number projected to rise dramatically without intervention. The overuse and misuse of antibiotics are major drivers of AMR, leading to the emergence of multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. These resistant pathogens, often belonging to the ESKAPE group (Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and Enterobacter), are particularly problematic due to their high mortality rates and limited treatment options. The situation is exacerbated by the ability of many bacteria to form biofilms, which provide a protective environment that enhances resistance to antibiotics by up to 1000-fold. This increased resistance translates into longer illness durations, higher mortality rates, and increased healthcare costs. The development of new antimicrobial agents and innovative strategies for antibiotic delivery and targeting is crucial to combat this crisis. Nanotechnology, with its ability to create novel drug delivery systems and antimicrobial agents, presents a hopeful avenue for tackling this challenge. The unique size, surface properties, and biocompatibility of nanoparticles (NPs) offer potential advantages over conventional antibiotics, allowing for targeted drug delivery, enhanced penetration of biofilms, and reduced toxicity. This review delves into the current advancements in nanotechnology for combating MDR and biofilm infections.

The existing literature extensively documents the global threat of antimicrobial resistance and the urgent need for novel therapeutic strategies. Studies highlight the mechanisms of antibiotic resistance in bacteria, including enzyme production, decreased antibiotic uptake, target alteration, efflux pump overexpression, and biofilm formation. The ESKAPE pathogens are consistently identified as major contributors to hospital-acquired infections and mortality. Several reviews have explored the potential of nanotechnology in combating bacterial infections. These studies emphasize the advantages of nanoparticles for delivering antibiotics, enhancing their efficacy, and overcoming resistance mechanisms. Specific types of nanoparticles, such as silver, gold, zinc oxide, and others, have demonstrated antimicrobial activity through various mechanisms, including membrane disruption, ROS generation, and intracellular component targeting. The literature also highlights the synergistic effects of combining nanoparticles with conventional antibiotics, further enhancing their antimicrobial action and potentially overcoming existing resistance.

This review article employed a systematic approach to gather and analyze existing literature related to the use of nanotechnology in combating multidrug-resistant bacteria. The authors conducted a comprehensive search of relevant databases, including PubMed, Web of Science, and Scopus, using keywords such as "nanotechnology," "antibiotic resistance," "multidrug-resistant bacteria," "biofilm," and various nanoparticle types (e.g., silver nanoparticles, gold nanoparticles). The search was limited to articles published in peer-reviewed journals, focusing on in vitro and in vivo studies investigating the antimicrobial activity of nanoparticles against MDR bacteria and biofilms. Inclusion criteria for selected studies included the use of well-characterized nanoparticles, demonstrable antimicrobial activity against MDR bacterial strains, and studies employing rigorous experimental methodologies. The collected data were meticulously analyzed to identify trends, summarize findings, and identify knowledge gaps. The review synthesizes information on the different types of nanoparticles (organic, inorganic, hybrid), their mechanisms of action (membrane disruption, ROS generation, intracellular targeting), and their synergistic effects when combined with conventional antibiotics. The authors also critically evaluate the strengths and limitations of using nanotechnology to combat bacterial resistance and offer perspectives on future research.

This review summarizes key findings regarding the application of nanotechnology in fighting multidrug-resistant bacteria: **Mechanisms of Antibiotic Resistance:** The review details the diverse mechanisms bacteria use to develop resistance to antibiotics, including enzyme production that degrades antibiotics (like β-lactamases), reduced antibiotic uptake, target site alteration, efflux pump activation that expels antibiotics from the cell, and the formation of protective biofilms. **Nanoparticle Types and Formulations:** The review categorizes nanoparticles into organic (liposomes, polymeric nanoparticles, micelles), inorganic (metal and metal oxide nanoparticles), and hybrid nanoparticles. It describes their various formulations and methods of synthesis. Silver nanoparticles (AgNPs) are highlighted as the most extensively studied and used. **Mechanisms of Nanoparticle Action:** Nanoparticles exert their antimicrobial effects through multiple mechanisms, including disruption of bacterial cell walls and membranes, the generation of reactive oxygen species (ROS) leading to oxidative stress, damage to intracellular components (proteins, DNA, enzymes, mitochondria), interference with efflux pumps, inhibition of the electron transport chain, and disruption of biofilm architecture. The surface charge of nanoparticles significantly influences their interaction with bacteria and biofilm matrices; positively charged NPs generally show improved penetration into the anionic biofilm matrix. **Synergistic Effects of Nanoantibiotics:** Combining nanoparticles with conventional antibiotics often produces synergistic effects, enhancing the antibacterial activity and potentially circumventing resistance mechanisms. The review presents examples of such synergistic combinations, including AgNPs with amoxicillin and ampicillin, PLGA nanoparticles with gentamicin, and alginate nanoparticles with colistin. The enhanced efficacy is attributed to the nanoparticle's role in targeted drug delivery, protecting antibiotics from degradation, and improving penetration into bacterial cells. **Effect on Planktonic Bacteria, Intracellular Bacteria, and Biofilms:** Nanoparticles effectively combat planktonic bacteria, particularly ESKAPE pathogens, through the mechanisms described above. Their ability to penetrate host cells allows for treatment of intracellular infections caused by bacteria like Salmonella and Mycobacterium tuberculosis. Nanoparticles effectively penetrate and disrupt the protective extracellular polymeric matrix of biofilms, leading to biofilm eradication. **Strengths and Challenges:** The use of nanoparticles offers significant advantages over conventional antibiotics, including targeted delivery, sustained release, and reduced dosage. However, challenges remain concerning long-term toxicity, optimal dosage, suitable routes of administration, detailed understanding of cellular uptake mechanisms, and cost-effectiveness.

The findings of this review strongly support the potential of nanotechnology to address the pressing issue of antibiotic resistance. The multifaceted mechanisms of action exhibited by various nanoparticles, particularly their ability to overcome resistance mechanisms and enhance antibiotic efficacy, offer a significant advancement over conventional therapies. The synergistic effects observed when combining nanoparticles with existing antibiotics are particularly promising, suggesting a strategy for repurposing existing drugs and expanding their therapeutic range. The ability of nanoparticles to target biofilms and intracellular bacteria further expands their potential applications. However, the challenges related to long-term toxicity and the need for comprehensive understanding of the complex interactions between nanoparticles and biological systems necessitate further research. Standardization of nanoparticle characterization and rigorous preclinical and clinical trials are crucial to ensure safe and effective translation of this technology into clinical practice. The economic considerations of developing and implementing these novel therapies also require careful attention.

Nanotechnology presents a novel and promising approach to combat the escalating threat of multidrug-resistant bacteria. The unique properties of nanoparticles offer significant advantages in overcoming resistance mechanisms, enhancing antibiotic efficacy, and targeting diverse bacterial forms. While challenges related to toxicity and delivery remain, ongoing research promises to refine nanoparticle design and optimize their therapeutic potential. Future research should focus on detailed mechanistic studies, development of biocompatible and biodegradable nanoparticles, rigorous in vivo studies, and well-designed clinical trials to pave the way for widespread clinical adoption of nanoantibiotics.

This review is limited to the currently available literature on the topic. The field of nanotechnology in antimicrobial therapy is rapidly evolving, and new findings and advancements continue to emerge. Furthermore, the interpretation of results from in vitro studies may not always accurately reflect in vivo outcomes, necessitating comprehensive in vivo studies and clinical trials to validate efficacy and safety. The economic feasibility of large-scale production and implementation of nanomaterial-based therapies also requires careful consideration.