**Background:** Multidrug-resistant (MDR) bacteria pose a major threat to global health, driven by the overuse and misuse of conventional antibiotics. The development of new antibiotics has lagged far behind the emergence of resistance, creating an urgent need for novel antimicrobial strategies. Nanomaterials (NMs) have emerged as promising candidates due to their unique physicochemical properties, multiple antibacterial mechanisms, and low potential for inducing resistance. This review provides a comprehensive overview of the mechanisms of antibiotic resistance, recent advances in nanoantibiotics (including inorganic, organic, and composite NMs), and the challenges related to biosafety and large-scale manufacturing.
**Methods:** This is a narrative review that synthesizes findings from a wide range of published studies. The authors first describe the major mechanisms of antibiotic resistance: emergence of resistance genes (e.g., via horizontal gene transfer, biofilms, SOS response), change of antibiotic targets (e.g., mutations in 23S rRNA, penicillin-binding proteins), formation of penetration barriers (e.g., porin mutations), degradation of antibiotics (e.g., β-lactamases), and adjustment of efflux pump systems. They then categorize and discuss various nanoantibiotics: inorganic NMs (metal-based: Ag, Au, alloy, metal oxide/sulfide; carbon-based: fullerenes, carbon quantum dots, carbon nanotubes, graphene, MXene, covalent organic frameworks, nanodiamonds), organic NMs (natural: chitosan; synthetic: PLGA, PCL, PEG, conductive polymers), and composite NMs (metal-based nanocomposites like MOFs, polymer-based nanocomposites, and other hybrids). The review also covers bioeffects and biosafety at the cell, organ, and body levels, as well as methods for large-scale manufacturing of these NMs.
**Key Results:** The review presents extensive data on the antibacterial efficacy of various NMs. For example, glutathione-stabilized silver nanoparticles (GSH-Ag NPs) showed MICs ranging from 4.92 to 39.4 μg mL⁻¹ against MDR *Campylobacter* strains. Aminoglycoside-functionalized Ag NPs (AgNPs@amikacin) had MICs ≤ 0.5 μg mL⁻¹ and reduced *Acinetobacter baumannii* biofilm metabolic activity by over 50%. Vancomycin-modified Au NPs improved efficacy against vancomycin-resistant *Enterococci* by more than 60 times compared to vancomycin alone. Quaternary ammonium carbon quantum dots (qCQDs) exhibited broad-spectrum activity with MICs ranging from 12.5 to 50 μg mL⁻¹ against various bacteria. Chitosan-based NMs showed significant biofilm inhibition, e.g., low molecular weight chitosan inhibited *S. aureus* V329 biofilm by 32.9% to 88.7% at 400–1600 μg mL⁻¹. The review also notes that Au NPs synthesized *in vivo* had a median lethal dose of 920 mg kg⁻¹, about 100 times their effective dose (7.2 mg kg⁻¹), indicating high biosafety. For large-scale production, methods such as solid-state reactions, microfluidics, and ball milling have achieved yields of up to 600 kg for ZnO NPs and 120 grams for CuO NPs.
**Clinical Implications:** Nanoantibiotics represent a transformative approach to combating MDR bacterial infections. Their ability to act through multiple mechanisms simultaneously reduces the likelihood of resistance development. However, clinical translation faces significant hurdles, primarily biosafety concerns and the need for scalable, cost-effective manufacturing. The review emphasizes that future research should focus on improving specificity to pathogenic bacteria, elucidating clear antibacterial mechanisms, and ensuring high biosafety through comprehensive profiling of physicochemical properties, biodistribution, and pharmacokinetics. Interdisciplinary collaboration is essential to advance nanoantibiotics from the laboratory to clinical practice, potentially offering a powerful arsenal against the growing threat of antimicrobial resistance.