Polymyxin B-antioxidant nanoassemblies mitigate nephrotoxicity and attenuate sepsis-induced acute lung injury.

Sepsis is a life-threatening syndrome in which dysregulated host responses drive organ dysfunction; acute lung injury (ALI) is both the most prevalent and the most fatal manifestation. Here we synthesize an ester-linked α-tocopherol-gallic acid conjugate (VE-GA) and co-assemble it with polymyxin B (PMB) to yield composite nanoparticles (PV NPs). PV NPs integrate PMB-mediated antibacterial activity and endotoxin (LPS) neutralization with VE-GA-enabled broad-spectrum reactive oxygen species (ROS) scavenging while mitigating the dose-limiting nephrotoxicity of PMB and prolonging pulmonary retention. In vitro, PV NPs preserve PMB's bactericidal and LPS-binding functions and markedly reduce ROS and pro-inflammatory mediators. In murine models, PV NPs attenuate lung inflammation and oxidative stress in LPS-induced ALI and, in the cecal ligation-and-puncture model of polymicrobial sepsis, confer a 75% survival rate, significantly outperforming either component alone. These data highlight PV NPs as a multi-mechanistic and translational strategy for sepsis/ALI that couples synergistic pharmacodynamics with an improved safety profile.