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.

Micropatterns and peptide gradient on the inner surface of a guidance conduit synergistically promotes nerve regeneration in vivo

Both of the surface topographical features and distribution of biochemical cues can influence the cell-substrate interactions and thereby tissue regeneration in vivo.However,they have not been combined simultaneously onto a biodegradable scaffold to demonstrate the synergistic role so far.In this study,a proof-of-concept study is performed to prepare micropatterns and peptide gradient on the inner wall of a poly(D,L-lactide-co-caprolactone)(PLCL)guidance conduit and its advantages in regeneration of peripheral nerve in vivo.After linear ridges/grooves of 20/40μm in width are created on the PLCL film,its surface is aminolyzed in a kinetically controlled manner to obtain the continuous gradient of amino groups,which are then transferred to CQAASIKVAV peptide density gradient via covalent coupling of glutaraldehyde.The Schwann cells are better aligned along with the stripes,and show a faster migration rate toward the region of higher peptide density.Implantation of the nerve guidance conduit made of the PLCL film having both the micropatterns and peptide gradient can significantly accelerate the regeneration of sciatic nerve in terms of rate,function recovery and microstructures,and reduction of fibrosis in muscle tissues.Moreover,this nerve conduit can also benefit the M2 polarization of macrophages and promote vascularization in vivo.