Sonotheranostic nanosideromycin eradicates bacterial biofilm infections via ultrasound-detonated ROS generation and ferroptosis-like death

Biofilm formation poses a severe challenge to antibacterial stewardship. While siderophore-antibiotic conjugates (termed as sideromycins) offer a promising solution, their efficacy is inherently limited by antibiotic resistance. To transcend this barrier, we pioneer a transformative siderophore-sonosensitizer conjugate through covalent linkage of a catechol siderophore to purpurin 18 (a sonosensitizer). This novel conjugate further self-assembles with iron(III) ions, forming the first-reported carrier-free nanosideromycin—an all-in-on iron-siderophore-sonosensitizer nanoplatform. This design enables ultrasound-denotated reactive oxygen species (ROS) generation and ferroptosis-like amplication. Capitalizing on bacteria-specific siderophore uptake and pH-responsive assembly/disassembly, the nanosideromycin enables precision delivery and active internalization of sonosensitizers into bacteria. This strategy permits real-time localization of infections via concurrent fluorescence/photoacoustic and magnetic resonance imaging. Upon ultrasound irradiation, dual antimicrobial mechanisms of sonosensitizer-mediated sonodynamic therapy and siderophore/iron-augmented sono-Fenton catalysis are stimuonously unleashed, synergistically tirggering an explosive ROS burst and potent ferroptosis-like bacterial death. As a result, mice with multidrug-resistant biofilm-induced pyomyositis were completely cured. Collectively, this first-in-class theranostic nanosideromycin integrates highly-targeted imaging diagnostics, cost-effective yet ultra-efficient ROS generation, and ferroptosis-like bacterial killing, establishing a paradigm-shifting strategy for biofilm therapy with spatiotemporal controllability. A diagram illustrating FSP nanosideromycin for noninvasive imaging diagnosis and US-activated eradication of MDR biofilm infections. This FSP nanosideromycin is constructed through Fe(III)-coordinated self-assembly of a hybrid sideromycin, which covalently integrates a catechol siderophore with the sonosensitizer purpurin 18. Capitalizing on bacterial siderophore-specific uptake and pH-responsive assembly/disassembly characteristics, FSP nanosideromycin achieves targeted intracellular co-delivery of both sonosensitizers and iron ions. This dual delivery enables precise localization of infection sites via in situ fluorescence/photoacoustic imaging and magnetic resonance imaging (MRI). Upon US irradiation, the system simultaneously activates sonosensitizer-mediated sonodynamic reaction and siderophore-catalyzed sono-Fenton reaction. These synergistic processes trigger an explosive burst of localized reactive oxygen species (ROS) and bacterial ferroptosis-like bacterial killing, resulting in efficient biofilm eradication. • A novel siderophore-sonosensitizer nanoconjugate (FSP) hijacks bacterial iron-uptake for targeted delivery. • Ultrasound precisely triggers robust ROS generation via sonodynamic action and siderophore-mediated sono-Fenton reaction. • Iron overload synergizes with ROS to potently induce bacterial ferroptosis-like death. • The nanosideromycin FSP enables tri-modal imaging and sonotherapy against MDR biofilm infections.