Engineered Biomimetic Nanomicelles Target Inflammation in Sepsis-Associated Acute Lung Injury by Scavenging ROS and Reprogramming Macrophages

Quan Li,1,* Haijun Sun,1,* Xinjing Zhang,2,* Yani Chen,1 Zhifeng Wu,1 Maohong Xia,1 Lu Sun,1 Weigang Shi,1 Zhaorui Sun,3 Wei Li,4 Lili Ding1 1Intensive Care Unit, Jiangsu Province (Suqian) Hospital, Suqian, Jiangsu, 223899, People’s Republic of China; 2Pulmonary and Critical Care Medicine, Jiangsu Province (Suqian) Hospital, Suqian, Jiangsu, 223899, People’s Republic of China; 3Department of Emergency Medicine, Jinling Hospital, Medical School of Nanjing University, Nanjing, Jiangsu, 210093, People’s Republic of China; 4Department of Emergency Medicine, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu, 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Li, Email [email protected] Lili Ding, Email [email protected]: Sepsis-associated acute lung injury (SALI) has high mortality, largely driven by a damaging cycle of oxidative stress and inflammation, with a lack of effective treatments. To address this, a novel biomimetic nanodrug was developed. It uses an amphiphilic copolymer (PT) to encapsulate the antioxidant/anti-inflammatory agent carnosic acid (CA), forming PT@CA micelles. These micelles are then coated with M2 macrophage membranes (MM) to create MM@PT@CA. Compared to traditional liposomes, the macrophage membrane has better inflammatory targeting and biological safety.Methods: The PT copolymer was synthesized by grafting thioctic acid onto polylysine. CA was encapsulated via anti-solvent precipitation to form PT@CA, which was subsequently coated with M2 macrophage membranes via co-extrusion to yield the final bionic nanomicelle, MM@PT@CA. The system’s ROS-responsive drug release, antioxidant, and antibacterial activities were characterized. Its biocompatibility, ability to scavenge cellular ROS, anti-inflammatory effects, and promotion of M2 macrophage polarization were assessed in vitro. Therapeutic efficacy was further evaluated in a mouse model of sepsis-induced lung injury.Results: MM@PT@CA demonstrated significant multifunctional efficacy across a series of experiments. In vitro, it scavenged DPPH and ABTS radicals by 74.07% and 91.47%, respectively, and inhibited the growth of Staphylococcus aureus and Escherichia coli. It was efficiently taken up by cells and accumulated at inflammatory sites. Moreover, it exhibited excellent biocompatibility, remarkably restoring cell viability under oxidative stress from 48.70% to 93.85% while down-regulating pro-inflammatory factors. In vivo, MM@PT@CA treatment reduced apoptosis from 28.79% to 5.49%. Notably, the progression of SALI was effectively halted, which was attributed to its ability to modulate macrophage polarization and inhibit the pro-inflammatory cytokine storm.Conclusion: The developed bionic nanomicelle targets inflammation, combats infection and oxidative stress, and ultimately alleviates SALI. These features highlight MM@PT@CA promising therapeutic potential for the treatment of SALI. Keywords: acute lung injury, biomimetic nanomicelles, ROS scavenging, macrophage reprogramming, carnosic acid