Plant-Derived Flavonoidand Antibiotic Self-AssembledNanomedicines for Enhanced Efficacy Against Bacterial Infections

Bacterial infections pose a serious challenge to public health and contribute to significant economic losses. The limited solubility of many antibiotics affects their absorption and therapeutic potential. Nanobased delivery systems offer a promising approach to improve solubility and therapeutic efficacy, though challenges such as nanocarrier toxicity and low drug loading rates remain. Here, we present a carrier-free drug delivery strategy to enhance the antibacterial efficacy. Two poorly water-soluble drugs, rifampicin (RIF) and isobavachalcone (IBC), were formulated into nanoparticles (RI@NP), with sodium lauryl sulfate and ammonium acetate added to improve the stability and polarity. RI@NP demonstrated superior efficacy at lower doses compared with RIF and IBC alone. Mechanistic studies revealed that RI@NP disrupts bacterial membrane integrity, leading to PMF collapse, impaired electron transport, ATP depletion, intracellular ROS accumulation, and ultimately bacterial cell death. Furthermore, RI@NP effectively eliminated 99% of Staphylococcus aureus within 24 h. Compared to the separate use of RIF and IBC, RI@NP showed enhanced efficacy in the mouse peritonitis-sepsis model, with a 100% survival rate and a 99% reduction in bacterial load in major organs. Our designed carrier-free RI@NP could achieve enhanced efficacy and shed light on the development of carrier-free nanoparticles against bacterial infections.