Advances in drug delivery systems for intracellular infections: minimizing antibiotic dependency

Effective treatment of intracellular bacterial infections remains a global challenge, as host cell barriers limit the accessibility of conventional antibiotics, necessitating innovative drug delivery systems (DDS) to enhance therapeutic efficacy. Current strategies for treating intracellular bacterial pathogens, such as Mycobacterium tuberculosis and Staphylococcus aureus, primarily rely on high-dose or long-term antibiotic use. However, the poor intracellular delivery efficiency of antibiotics and the emergence of resistance mechanisms significantly reduce their therapeutic efficacy and may cause adverse drug reactions. While alternative approaches like antimicrobial peptides and phage therapy have been proposed, their clinical utility is often limited by suboptimal stability and high production costs. Consequently, developing precision-targeted delivery platforms to enhance the intracellular accumulation and retention time of antibiotics is a critical approach to minimizing antibiotic dependency while maintaining potent antibacterial activity. These strategies aim to reduce antibiotic use while maintaining equivalent therapeutic efficacy, thereby minimizing the spread of antibiotic resistance. This review focuses on advanced drug delivery systems designed to overcome cellular penetration barriers and restore antibiotic efficacy. It systematically summarizes recent advancements in the field, evaluating the strengths of current delivery strategies, especially nanotechnology and antibiotic conjugation. Particular emphasis is placed on the potential of emerging technologies, including smart delivery platforms, to advance intracellular infection therapy. Furthermore, the review identifies existing challenges and provides future perspectives, outlining the path toward safer and more effective strategies for eradicating intracellular bacterial infections.