Preparation Of Anti-Inflammatory Nanodrugs For Suppressing Cytokine Storm

Defined as a life-threatening organ dysfunction due to a dysregulated host response to infection,sepsis affects nearly 30 million lives each year,consuming a large amount of healthcare expenditure and increasing the healthcare burden on society.In particular,sepsis has a mortality rate of up to 10%in some low-and middle-income countries and in some patients with underlying diseases.In the face of such a lifethreatening disease,there is an urgent need for effective sepsis treatment strategies to reduce its mortality.The most typical pathological state in patients with sepsis is inflammatory overstimulation and the subsequent cytokine storm.When a patient is infected,the innate immune system,led by immune cells,recognizes pathogenassociated molecular patterns(PAMPs)through pattern recognition receptors(PRRs)that trigger immune cell cascade transduction signals and activate the immune system to produce a storm of inflammatory mediators and cytokines,including damageassociated molecular patterns(DAMPs).An overactive immune state in the body induces the following conditions:mitochondrial dysfunction with high production of reactive oxygen species(ROS);neutrophil formation of neutrophil extracellular traps(NETs)and subsequent NET apoptosis(NETosis)process releasing free nucleic acids(cfDNA)and histones;impaired endothelial cell function and abnormal cellular oxygen metabolism.The presence of the source of infection as well as a large number of inflammatory mediators causes the organism to enter a state of immune disorder,affecting the function of various organs and causing multi-organ failure.If the source of infection can be removed and inflammatory mediators eliminated in a timely manner during the process of infection,the excessive inflammatory response in the body can be alleviated and the production of cytokine storm can be suppressed,thus achieving the treatment of sepsis.In this paper,we designed multifunctional anti-inflammatory materials to control inflammation and alleviate cytokine storm by removing multiple inflammatory mediators.First,we prepared PLGA@Cur nanoparticles with a particle size of approximately 300 nm using poly(lactic-co-glycolic acid)(PLGA)encapsulated with the antiinflammatory agent curcumin(Cur)to verify its antioxidant and anti-inflammatory effects at the cellular level.Secondly,we prepared TMPP nanoparticles using tannic acid(TA),Mn2+,polymyxin B(PMB)and polyvinylpyrrolidone(PVP)as constituents and exploited their non-covalent interactions.It was verified that TMPP can scavenge various inflammatory mediators such as lipopolysaccharide(LPS),free nucleic acid(cfDNA)and reactive oxygen species(ROS)in addition to its antibacterial properties,effectively alleviating inflammation at the cellular level.We used TMPP in an in vivo inflammation model in mice,and the results of the acute lung injury(ALI)model showed that the material effectively alleviated lung inflammation and significantly reduced lung cytokine levels.The treatment results of cecum puncture ligation(CLP)model showed that the mice survived longer,had improved survival status,and decreased the level of inflammatory mediators in vivo after treatment.The above results show that TMPP exhibits versatility in the treatment of systemic sepsis in mice,inhibiting both the production of systemic cytokine storm and alleviating multi-organ damage in mice,successfully achieving a comprehensive sepsis treatment.Our work strongly demonstrates the effectiveness of targeting multiple inflammatory mediators to modulate cytokine storm.