ROS-responsive nanoparticles for targeted delivery of PICK1 plasmid to ameliorate sepsis-induced coagulopathy

Sepsis-induced coagulopathy (SIC) is characterized by excessive inflammation, oxidative stress, and microthrombus formation, and its clinical management remains challenging. Protein interacting with C kinase 1(PICK1) has been shown to suppress inflammatory responses and ROS generation, suggesting that targeted modulation of PICK1 may represent a promising therapeutic strategy for SIC. However, given the broad expression of PICK1 across multiple tissues, effective approaches for its targeted delivery and modulation remain lacking. Herein, we developed ROS-responsive amphiphilic polymer nanoparticles (TD@pDNA NPs) for targeted delivery of PICK1 plasmid DNA (PICK1 pDNA) to SIC lesions. The nanoparticles were self-assembled from the amphiphilic polymer TD-synthesized via coupling of N1-(4-boronobenzyl)-N3-(4-boronophenyl)-N, N, N', N'-tetramethylpropane-1,3-diamine with 1,2-decanediol-and PICK1 pDNA. TD@pDNA NPs showed ROS-triggered degradation, ROS-scavenging, and protection of PICK1 pDNA from nuclease digestion. In vitro, TD@pDNA NPs had low cytotoxicity, efficient transfection, suppressed LPS-induced cytokine release, inhibited TLR4/NF-κB activation, and reduced intracellular ROS. In vivo, TD@pDNA NPs improved survival and body weight in cecal ligation and puncture mice, reduced systemic inflammation and tissue ROS, restored coagulation, suppressed microthrombosis, and displayed good hemocompatibility and organ biocompatibility. Collectively, TD@pDNA NPs effectively target multiple pathological processes of SIC by integrating gene delivery, ROS scavenging, anti-inflammatory, and anticoagulant functions, thereby providing a safe and effective nanoplatform for SIC therapy.