A Synergistic Nanotherapeutic Platform Leveraging Bioorthogonal Amplification and Ultrasound Triggering for Multidrug‐Resistant Bacterial Clearance and Wound Repair

Abstract

The rise of multidrug‐resistant (MDR) bacterial infections highlights the need for precise, non‐antibiotic therapeutic strategies. Herein, a bioorthogonal reaction‐mediated and ultrasound (US)‐responsive nanoplatform (denoted as MnCyNPs‐Tz) was developed for synergistic antibacterial therapy. The platform encapsulates a multifunctional tricarbonyl Mn(I)‐cyanine complex (Mn‐Cy7) within tetrazine (Tz)‐functionalized DSPE‐PEG2000. Its targeting mechanism relies on a two‐step process: bacteria are first pre‐labeled with trans‐cyclooctene‐polyethylene‐glycol4‐phenylboronic acid (TCO‐PBA), enabling rapid, covalent, and enhanced anchoring of MnCyNPs‐Tz via the Tz‐TCO bioorthogonal reaction. DFT calculations indicated that incorporation of the IR‐780 ligand facilitates US‐triggered generation of hydroxyl radicals (·OH) and release of carbon monoxide (CO), underpinning a synergistic Type‐I sonodynamic and gas therapy. In vitro, the targeted system demonstrated potent efficacy against methicillin‐resistant Staphylococcus aureus (MRSA) by disrupting bacterial membranes and biofilms. Transcriptomic analysis revealed that it selectively interferes with bacterial oxidative stress responses, disrupts the respiratory chain and energy metabolism, and impairs membrane integrity, without inducing antibiotic resistance. In a murine MRSA‐infected wound model, US activation of the platform reduced bacterial burden (∼1% survival rate) and accelerated wound repair, achieving 99.1% closure within 10 days, alongside promoted tissue regeneration. This work presents a bioorthogonal reaction‐amplified, US‐activated strategy as a precise and effective antibiotic‐free alternative against MDR infections.