A conjugate strategy capable of targeting bacteria and selectively being activated at infection sites

• • LaP-Col achieved a maximum tolerated dose (MTD) >20-fold higher than colistin and minimal nephrotoxicity, directly addressing the dose-limiting toxicity that restricts colistin to last-resort status and enabling safer intravenous administration. • • In a murine P. aeruginosa pneumonia model, intravenous LaP-Col accumulated in infected lungs and significantly reduced lung injury scores compared to infected controls (p < 0.05), demonstrating infection-site targeting and therapeutic efficacy. • • The ROS-responsive phenylboronic acid linker enables selective activation at infection sites where elevated ROS levels cleave the linker, releasing active colistin; this contrasts with the slow, non-selective hydrolysis of colistin methanesulfonate, which compromises antibacterial efficacy. • • The lactosyl moiety confers bacterial targeting, likely via lectin-like interactions, enhancing drug accumulation at infection foci and improving survival rates in vivo, as evidenced by improved mouse survival in the pneumonia model.