ROS-responsive 18β-glycyrrhetic acid-conjugated polymeric nanoparticles mediate neuroprotection in ischemic stroke through HMGB1 inhibition and microglia polarization regulation

Ischemic stroke is an acute and serious cerebral vascular disease,which greatly affects people’s health and brings huge economic burden to society.Microglia,as important innate immune components in central nervous system(CNS),are double-edged swords in the battle of nerve injury,considering their polarization between pro-inflammatory M1 or anti-inflammatory M2 phenotypes.High mobility group box 1(HMGB1)is one of the potent pro-inflammatory mediators that promotes the M1 polarization of microglia.18β-glycyrrhetinic acid(GA)is an effective intracellular inhibitor of HMGB1,but of poor water solubility and dose-dependent toxicity.To overcome the shortcomings of GA delivery and to improve the efficacy of cerebral ischemia therapy,herein,we designed reactive oxygen species(ROS)responsive polymer-drug conjugate nanoparticles(DGA)to manipulate microglia polarization by suppressing the translocation of nuclear HMGB1.DGA presented excellent therapeutic efficacy in stroke mice,as evidenced by the reduction of infarct volume,recovery of motor function,suppressed of M1 microglia activation and enhanced M2 activation,and induction of neurogenesis.Altogether,our work demonstrates a close association between HMGB1 and microglia polarization,suggesting potential strategies for coping with inflammatory microglia-related diseases.

C-176 loaded Ce DNase nanoparticles synergistically inhibit the cGAS-STING pathway for ischemic stroke treatment

The neuroinflammatory responses following ischemic stroke cause irreversible nerve cell death.Cell free-double strand DNA(dsDNA)segments from ischemic tissue debris are engulfed by microglia and sensed by their cyclic GMP-AMP synthase(cGAS),which triggers robust activation of the innate immune stimulator of interferon genes(STING)pathway and initiate the chronic inflammatory cascade.The decomposition of immunogenic dsDNA and inhibition of the innate immune STING are synergistic immunologic targets for ameliorating neuroinflammation.To combine the anti-inflammatory strategies of STING inhibition and dsDNA elimination,we constructed a DNase-mimetic artificial enzyme loaded with C-176.Nanoparticles are self-assembled by amphiphilic copolymers(P[CL35-b-(OEGMA20.7-co-NTAMA14.3)]),C-176,and Ce^(4+)which is coordinated with nitrilotriacetic acid(NTA)group to form corresponding catalytic structures.Our work developed a new nano-drug that balances the cGAS-STING axis to enhance the therapeutic impact of stroke by combining the DNase-memetic Ce^(4+)enzyme and STING inhibitor synergistically.In conclusion,it is a novel approach to modulating central nervus system(CNS)inflammatory signaling pathways and improving stroke prognosis.