Bacteria-Responsive Nanostructured Drug Delivery Systems for Targeted Antimicrobial Therapy.

Bacteria exhibit adaptive phenotypic traits that confer resistance to host defenses and antimicrobial therapies. In response to the global threat of antimicrobial resistance, bacteria-responsive nanostructured drug delivery systems have emerged as a promising alternative to conventional broad-spectrum antimicrobials. These systems release therapeutics selectively in response to bacterial presence or to their secreted enzymes, toxins, antigens, or extracellular biomarkers, enabling precise activation at infection sites while minimizing off-target effects. Bacterial components such as membrane proteins, signaling molecules, biofilm-associated glycolipids, and enzymes (e.g., lipase, hyaluronidase) serve as triggers for these smart carriers. Exopolysaccharides are also commonly targeted using nanocarriers with complementary recognition elements. Such systems are often surface-modified or loaded with antimicrobials for on-demand release. Benefits include enhanced selectivity, reduced side effects, improved biofilm penetration, higher intracellular accumulation, and potential for personalized therapy. A variety of materials-including lipid-based carriers, metal nanoparticles, polymer nanoparticles, and inorganic nanomaterials-have been engineered to release antimicrobials only in the presence of pathogenic bacteria, often offering dual therapeutic effects (e.g., anti-inflammatory). Furthermore, many platforms integrate multiple antimicrobial mechanisms, reducing the likelihood of resistance development. This review highlights recent preclinical studies validating bacteria-responsive nanosystems and underscores their advantages over passive drug delivery and conventional free antimicrobials.