Ultrasound-responsive renal-targeted nanoparticles deliver TAK-242 to inhibit NF-κB/NLRP3 signaling and attenuate sepsis-associated acute kidney injury.

Sepsis-associated acute kidney injury (SA-AKI) remains a major clinical challenge due to the lack of effective targeted therapies. In this study, we designed ultrasound-responsive, renal-targeted nanoparticles based on serine-modified liposomes co-loaded with the TLR4 inhibitor TAK-242 and perfluoropentane (LIPs-S@TAK/PFP). The nanoplatform enables controlled TAK-242 release under low-intensity focused ultrasound through ultrasound-targeted microbubble destruction, providing both therapeutic delivery and real-time imaging capability. In vitro studies using HK-2 cells demonstrated that the nanoparticles effectively downregulated TLR4, reduced NF-κB activation, suppressed pro-inflammatory cytokine secretion (TNF-α, IL-1β, IL-6), decreased reactive oxygen species (ROS) generation, and attenuated pyroptosis. In septic rat models, LIPs-S@TAK/PFP significantly improved renal function, as evidenced by reduced serum creatinine, blood urea nitrogen, and cystatin-C levels, while alleviating tubular injury. Histological and molecular analyses further revealed inhibition of NLRP3 inflammasome activation and pyroptotic markers, including Caspase-1 and GSDMD-N. Multi-omics profiling confirmed that treatment predominantly suppressed the TLR4/NF-κB/NLRP3 axis while enhancing antioxidant defense, reflected by increased superoxide dismutase and reduced malondialdehyde. Collectively, these findings demonstrate that ultrasound-responsive LIPs-S@TAK/PFP nanoparticles provide efficient renal-targeted delivery of TAK-242, mitigate inflammation and pyroptosis, and protect kidney function in SA-AKI. This strategy highlights a promising nanomedicine-based therapeutic approach for sepsis-induced organ injury.