Microenvironment-adaptive mechano-chemical nanoagent powered by ultrasound for on-demand antibacterial therapy

Developing a mode-switchable, non-antibiotic platform targeting specific bacterial infection stages is essential for precise antibacterial therapy while minimizing drug resistance. Herein, we present an ultrasound-responsive nanoagent based on BiOCl nanosheets doped with Fe (UBF), capable of adapting to different infection states via switching from mechanical antibacterial mode to mechano-chemical mode. In the early infection, UBF exhibits a mechanical mode to eliminate dominant planktonic bacteria through ultrasound-induced propulsion, causing extracellular membrane disruption and intracellular oxidative stress. Additionally, it physically inhibits biofilm formation by preventing bacterial aggregation and reducing their secretion of critical components (eDNA and polysaccharides) for extracellular polymeric substances (EPS), thus preventing the infection from worsening. Once biofilms mature, endogenous hydrogen peroxide (H₂O₂) triggers the transition to mechano-chemical mode, where UBF catalyzes H₂O₂ into reactive oxygen species (ROS), the yield of which can be further enhanced by ultrasound. Concurrently, ultrasound disrupts the EPS matrix, allowing for deeper ROS penetration, killing bacteria within biofilms. This antibacterial strategy demonstrates self-adaption in vivo, preventing acute lung infections based on mechanical mode and achieving 97.1% healing efficiency for wound with chronic biofilm infections based on mechano-chemical mode. These findings highlight the potential of precision medicine, allowing treatment customization based on infection stages for improved healthcare outcomes. STATEMENT OF SIGNIFICANCE: This study develops an ultrasound-responsive nanoagent (UBF) that autonomously switches bactericidal modes to adapt to different infection stages. For planktonic bacteria, UBF is powered by controllable ultrasound to initiate a potent mechanical mode, achieving bacterial eradication through extracellular physical shearing and intracellular oxidative stress, while physically inhibiting biofilm formation by disrupting bacterial aggregation and EPS secretion. When encountering mature biofilms, UBF automatically transitions into a mechano-chemical mode activated by the overexpressed H₂O₂ in the infection microenvironment. Ultrasound further amplifies this synergistic mode, enabling UBF to mechanically perforate the dense EPS matrix and chemically eradicate deep-seated bacteria. This adaptive, antibiotic-free strategy demonstrates superior efficacy in both acute and chronic infection models, providing an advanced paradigm for combating multidrug-resistant infections.