Nucleic Acid-Based Antimicrobial Strategies Against Drug-Resistant Staphylococcus aureus: A Review of Mechanisms of Action and Delivery Approaches.

Drug-resistant Staphylococcus aureus remains one of the major clinical challenges in both community and hospital settings. Increasing rates of resistance to conventional antibiotics have prompted the development of alternative therapeutic strategies capable of selectively targeting essential bacterial functions. Nucleic acid-based antimicrobial strategies have emerged as promising and precise approaches, enabling the inhibition of gene expression, suppression of virulence, restoration of antibiotic susceptibility, and inhibition of bacterial growth in a sequence-specific manner. This review investigates various studies on antisense oligonucleotides (ASOs), small RNA-based approaches, and CRISPR-Cas systems against S. aureus, with a focus on their antimicrobial efficacy, mechanisms of action, and delivery strategies. These platforms can target genes involved in cell division, transcription, quorum sensing, biofilm formation, and antibiotic resistance. As efficient intracellular delivery remains a major barrier, multiple carriers-including cell-penetrating peptides, nanoparticles, liposomes, DNA nanostructures, and phagemid-based platforms-have been developed to enhance therapeutic efficacy. It has been demonstrated that optimized delivery systems can substantially improve the stability, cellular uptake, and antibacterial activity of nucleic acid therapeutics. Furthermore, the programmability and high target specificity of these agents is a step forward, facilitating the development of precision antimicrobial therapies with the potential for reduced effects on non-target bacterial populations. Overall, the available data support the potential of nucleic acid-based antimicrobials as promising preclinical adjuncts to conventional antibiotics for combating multidrug-resistant S. aureus.