Nano-Enabled Delivery of Phage-Based Antibacterials Against ESKAPE Pathogens

Antimicrobial resistance (AMR) remains a major clinical challenge, with <i>Enterococcus faecium</i>, <i>Staphylococcus aureus</i>, <i>Klebsiella pneumoniae</i>, <i>Acinetobacter baumannii</i>, <i>Pseudomonas aeruginosa</i>, and <i>Enterobacter</i> species (ESKAPE) accounting for a substantial share of multidrug-resistant (MDR) infections worldwide. These organisms undermine antibiotic efficacy through reduced permeability, surface shielding, biofilm formation, and rapid genetic adaptation, mechanisms that primarily restrict effective exposure at infection sites. Bacteriophages, phage-derived enzymes, and Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based antimicrobials provide selective and mechanistically distinct alternatives to conventional antibiotics, but their performance in vivo is often limited by instability in physiological environments, immune neutralization, uneven tissue distribution, and insufficient access to bacteria protected by biofilms or surface-associated barriers. This narrative review examines how nanotechnology-based delivery systems can address these constraints. We first outline the delivery-relevant biological barrier characteristic of ESKAPE pathogens, then summarize the therapeutic potential and inherent limitations of whole phages, phage-derived enzymes, and CRISPR-based antimicrobials when used without formulation. Major nanotechnology platforms for antibacterial delivery are reviewed, followed by analysis of how nano-enabled systems can improve stability, localization, and persistence of these biological agents. A pathogen-aware integration framework is presented that links dominant barriers in each ESKAPE pathogen to the biological modality and nano-enabled delivery strategy most likely to enhance exposure at infection sites. Translational challenges, regulatory considerations, and emerging directions, including responsive delivery systems and personalized approaches, are also discussed. Overall, nano-enabled phage-based therapeutics represent a realistic and adaptable strategy for managing MDR ESKAPE infections. Therapeutic success depends on both continued discovery and engineering of antibacterial agents and effective delivery design.