Functionalized Microsphere Platform Combining Nutrient Restriction and Combination Therapy to Combat Bacterial Infections

The escalating prevalence of multidrug-resistant (MDR) bacterial infections has emerged as a critical global health crisis, undermining the efficacy of conventional antibiotic therapies. This pressing challenge necessitates the development of innovative strategies to combat MDR pathogens. Advances in multifunctional drug delivery systems offer promising solutions to reduce or eradicate MDR bacteria. Inspired by the fact that the growth of bacteria requires essential nutrients, core–shell porous poly(lactic- co -glycolic acid) (PLGA) microspheres coated with pH-responsive polydopamine (PDA) were fabricated to improve delivery, resulting in enhanced efficacy through nutrient restriction and combination therapy. The PDA chelates iron ions in the environment, preventing bacteria from absorbing iron and thus suppressing their growth and proliferation. Subsequently, the released antibiotics from the porous PLGA core, rifampicin and polymyxin B, accelerate bacterial eradication by disrupting their inner and outer membrane structures. Such a multifunctional microsphere platform clears 99% Salmonella Typhimurium in 4 h and shows increased efficiency in a lethal intestinal infection model in mice. These findings provide a drug delivery system that integrates bacterial nutrient restriction and antibiotic killing, highlighting the potential of targeting bacterial iron regulation as a strategy for developing new antimicrobial delivery systems to address MDR bacterial infections.