TRIM21-dependent ultrasmall chiral gold nanoparticles for preventing microglia senescence against Alzheimer's disease

Tripartite motif 21(TRIM21)is an E3 ubiquitin ligase that shows great promise for protein degradation through ubiquitination.Here,ultrasmall chiral gold nanoparticles(D-or L-NPs)modified by D-or L-glutathione ligands were fabricated.After conjugated with an NLR family pyrin domain-containing protein 3(NLRP3)antibody(D-NP-a NLRP3 or L-NP-a NLRP3),DNP-a NLRP3 showed effective delivery efficiency of the antibody into microglia and prevented Aβ-mediated microglia senescence,and p16^(ink4a),a marker of senescence,in the microglia was reduced by 90.3%±7.8% while L-NP-a NLRP3 decreased by 48.01%±3.1%.Mechanistic investigations revealed that the D-NP-a NLRP3((1.5±0.3)×10^(7)M^(-1))exhibited sixteen-fold larger binding affinity to transmembrane glycoprotein SLC3A2 than L-type((9.5±2.7)×10^(5)M^(-1)),which led to a high efficiency of antibody delivery and TRIM21-dependent NLRP3 degradation.Notably,the blood-brain barrier(BBB)-crossing ability of chiral NP-a NLRP3 as well as NLRP3 degradation was demonstrated in vivo.The APP/PS1 Alzheimer's disease(AD)model mice experiments exhibited a reduction of 89.7%±6.8% for the NLRP3 protein and 84.2±7.5% for p16^(ink4a)following the intravenous administration of D-NP-a NLRP3 once a week for 60 days.Furthermore,the levels of the AD markers Aβ and phosphorylatedTau in the brains were reduced by 86.2%±8.2% and 81.6%±9.1%;these were 2.1-fold and 1.9-fold higher than those treated with L-NP-a NLRP3,respectively.The studies provide a method to rescue AD-like pathologies and prevent senescence.

Electromagnetic field-enhanced chiral dimanganese trioxide nanoparticles mitigate Parkinson’s disease

The misfolding and aggregation ofα-synuclein(α-syn)is closely associated with Parkinson’s disease(PD).Here,chiral dimanganese trioxide(Mn_(2)O_(3))nanoparticles(NPs)were prepared for PD treatment enhanced by a noninvasive electromagnetic field(MF).The affinity constants of D-NPs towardα-syn monomer(mono)orα-syn fibril were 3.5 times or 5.2 times higher,respectively,than those of L-NPs,and the mechanical force generated by NPs under a MF further promoted the interaction between NPs andα-syn to amplify the difference between L-NPs and D-NPs.As the synergy effect of the preferentially affinity ability and MF-induced mechanical forces,D-NPs exhibited a better inhibitory efficiency onα-syn fibrillization than L-NPs.Furthermore,after differentially cellular uptake of L-/D-NPs via the caveolin-mediated pathway,as reactive oxygen species(ROS)-scavengers,D-NPs possess higher efficiency in decreasing intracellular ROS level than L-NPs to provide higher cytoprotective efficiency to neuron cells.In vivo data showed that after treatment with D-NPs under a MF for 60 days,α-syn concentration in the cerebrospinal fluid of PD mice decreased 81%,while dopamine level in the brain of PD mice increased 2.3-fold.These findings indicated the potential of utilizing the synergic interplay of chiral NPs and MF for treating disease and opened a new path to explore the nanoscale chirality for regulating the biological effect.

Metabolic profile of chiral cobalt oxide nanoparticles in vitro and in vivo

In this study,we investigated the in vivo behaviors of chiral cobalt oxide nanoparticles(Co_(3)O_(4) NPs)stabilized with D-or L-cysteine(denoted D-or L-NPs,respectively),as representative chiral metal oxide NPs.Chiral Co_(3)O_(4) NPs exerted no observable cytotoxicity within the tested dose range.Both D-NPs and L-NPs were internalized by dendritic cells through caveola-dependent endocytosis,and L-NPs entered the cells faster than D-NPs.Significantly,a metabolic analysis indicated that chiral L-NPs had the same effect on the level of bile acids in the liver as D-NPs,which is attributed to the almost equal amount of farnesoid X receptor(FXR)induced by the chiral NPs.This study suggests that low chiroptical activity nanomaterials would not affect the metabolism and kinetics under physiological conditions even if there is some difference in their transport.

Chiral Cu_(x)Co_(y)S Supraparticles Ameliorate Parkinson’s Disease

Protein aggregation causes alpha-synuclein(α-syn)to change from its original physiological role to a pathological state,which is a potential pathogenic mechanism in Parkinson’s disease(PD).Chiral _(L/D)-Cu_(x)Co_(y)S supraparticles(_(L/D)-SPs)with a circular dichroism value of 35 mdeg at 805 nm were fabricated using a simple wet-chemical method.The _(L/D)-SPs prevented the α-syn monomers from forming fibrils and triggered the α-syn fibrils to turn into monomers under 808 nm near-infrared(NIR)light.In living MN9D cells,D-SPs reduced cellular damage,neuronal functional deficits,and neuron loss caused by α-syn fibrils after NIR spectroscopy treatment within 10 min to prevent α-syn aggregation.Significantly,the reactive oxygen species produced by _(D)-SPs were 1.42 times higher than those produced by _(L)-SPs.In vivo experiments showed that _(D)-SPs had a protective effect on neuron damage caused by α-syn aggregate deposition,reduced the symptoms in a mouse model of PD,and restored cognitive ability.After NIR light treatment,the amount of α-syn in a mouse model of PD decreased by more than 67.5%.At the same time,_(D)-SPs gradually decomposed into small nanoparticleswithin 60 days and were excreted through the blood-brain barrier.This discovery paves theway for the treatment of neurodegenerative diseases using chiral SPs under NIR light irradiation.