Enantiomer-dependent immunological response to chiral nanoparticles.

Chirality is a unifying structural metric of biological and abiological forms of matter. Over the past decade, considerable clarity has been achieved in understanding the chemistry and physics of chiral inorganic nanoparticles1-4; however, little is known about their effects on complex biochemical networks5,6. Intermolecular interactions of biological molecules and inorganic nanoparticles show some commonalities7-9, but these structures differ in scale, in geometry and in the dynamics of chiral shapes, which can both impede and strengthen their mirror-asymmetric complexes. Here we show that achiral and left- and right-handed gold biomimetic nanoparticles show different in vitro and in vivo immune responses. We use irradiation with circularly polarized light (CPL) to synthesize nanoparticles with controllable nanometre-scale chirality and optical anisotropy factors (g-factors) of up to 0.4. We find that binding of nanoparticles to two proteins from the family of adhesion G-protein-coupled receptors (AGPCRs)-namely cluster-of-differentiation 97 (CD97) and epidermal-growth-factor-like-module receptor 1 (EMR1)-results in the opening of mechanosensitive potassium-efflux channels, the production of immune signalling complexes known as inflammasomes, and the maturation of mouse bone-marrow-derived dendritic cells. Both in vivo and in vitro immune responses depend monotonically on the g-factors of the nanoparticles, indicating that nanoscale chirality can be used to regulate the maturation of immune cells. Finally, left-handed nanoparticles show substantially higher (1,258-fold) efficiency compared with their right-handed counterparts as adjuvants for vaccination against the H9N2 influenza virus, opening a path to the use of nanoscale chirality in immunology.

Tapered chiral nanoparticles as broad-spectrum thermally stable antivirals for SARS-CoV-2 variants.

The incessant mutations of viruses, variable immune responses, and likely emergence of new viral threats necessitate multiple approaches to novel antiviral therapeutics. Furthermore, the new antiviral agents should have broad-spectrum activity and be environmentally stable. Here, we show that biocompatible tapered CuS nanoparticles (NPs) efficiently agglutinate coronaviruses with binding affinity dependent on the chirality of surface ligands and particle shape. L-penicillamine-stabilized NPs with left-handed curved apexes display half-maximal inhibitory concentrations (IC50) as low as 0.66 pM (1.4 ng/mL) and 0.57 pM (1.2 ng/mL) for pseudo-type SARS-CoV-2 viruses and wild-type Wuhan-1 SARS-CoV-2 viruses, respectively, which are about 1,100 times lower than those for antibodies (0.73 nM). Benefiting from strong NPs-protein interactions, the same particles are also effective against other strains of coronaviruses, such as HCoV-HKU1, HCoV-OC43, HCoV-NL63, and SARS-CoV-2 Omicron variants with IC50 values below 10 pM (21.8 ng/mL). Considering rapid response to outbreaks, exposure to elevated temperatures causes no change in the antiviral activity of NPs while antibodies are completely deactivated. Testing in mice indicates that the chirality-optimized NPs can serve as thermally stable analogs of antiviral biologics complementing the current spectrum of treatments.

Tri-mode Responses to Reactive Oxygen Species In Vivo by Chiral Vanadium-Based Nanoparticles.

Reactive oxygen species (ROS) are closely associated with the redox balance of the physiological environment, and monitoring ROS can aid in the early diagnosis of many diseases, including cancer. In this study, chiral vanadium trioxide/vanadium nitride (V2O3/VN) nanoparticles (NPs) modified with an organic dye (cyanine 3 [Cy3]) were prepared for ROS sensing. Chiral V2O3/VN NPs were prepared with the "ligand-induced chirality" strategy and showed a g-factor of up to 0.12 at a wavelength of 512 nm. To the best of our knowledge, this g-factor is the highest value of all chiral ceramic nanomaterials. The very high g-factor of the nanoprobe confers very high sensitivity, because the higher g-factor, the higher sensitivity. In the presence of ROS, V3+ in the chiral V2O3/VN nanoprobe undergoes a redox reaction to form V2O5, reducing the circular dichroism and absorbance signals, whereas the fluorescence signal of Cy3 is restored. With this nanoprobe, the limits of detection for the circular dichroic and fluorescence signals in living cells are 0.0045 nmol/106 and 0.018 nmol/106 cells, respectively. This chiral nanoprobe can also monitor ROS levels in vivo by fluorescence. This strategy provides an innovative approach to the detection of ROS and is expected to promote the wider application of chiral nanomaterials for biosensing.

Rapid and simultaneous detection of five mycotoxins and their analogs with a gold nanoparticle-based multiplex immuno-strip sensor.

Mycotoxins, as secondary metabolites produced by fungi, have been the focus of researchers in various countries and are considered to be one of the major risk factors in agricultural products. There is an urgent need for a rapid, simple and high-performance method to detect residues of harmful mycotoxins in agricultural foods. We have developed a gold nanoparticle-based multiplexed immunochromatographic strip biosensor that can simultaneously detect fifteen mycotoxins in cereal samples. With this optimized procedure, five representative mycotoxins, deoxynivalenol (DON), zearalenone (ZEN), T-2 toxin (T-2), tenuazonic acid (TEA) and alternariol (AOH) were detected in the range of 0.91-4.77, 0.04-0.56, 0.11-0.68, 0.12-1.02 and 0.09-0.75 ng/mL, respectively. The accuracy and stability of these measurements were demonstrated by analysis of spiked samples with recoveries of 91.8%-115.3% and coefficients of variation <8.7%. In addition, commercially available samples of real cereals were tested using the strips and showed good agreement with the results verified by LC-MS/MS. Therefore, Our assembled ICA strips can be used for the simultaneous detection of 5 mycotoxins and their analogs (15 mycotoxins in total) in grain samples, and the results were consistent between different types of cereal foods, this multiplexed immunochromatographic strip biosensor can be used as an effective tool for the primary screening of mycotoxin residues in agricultural products.

Interfacial Self-assembly of Chiral Selenide Nanomembrane for Enantiospecific Recognition.

Here, we report the synthesis of chiral selenium nanoparticles (NPs) using cysteine and the interfacial assembly strategy to generate a self-assembled nanomembrane on a large-scale with controllable morphology and handedness. The selenide (Se) NPs exhibited circular dichroism (CD) bands in the ultraviolet and visible region with a maximum intensity of 39.96 mdeg at 388 nm and optical anisotropy factors (g-factors) of up to 0.0013 while a self-assembled monolayer nanomembrane exhibited symmetrical CD approaching 72.8 mdeg at 391 nm and g-factors up to 0.0034. Analysis showed that a photocurrent of 20.97±1.55 nA was generated by the D-nanomembrane when irradiated under light while the L-nanomembrane generated a photocurrent of 20.58±1.36 nA. Owing to the asymmetric intensity of the photocurrent with respect to the handedness of the nanomembrane, an ultrasensitive recognition of enantioselective kynurenine (Kyn) was achieved by the ten-layer (10L) D-nanomembrane exhibiting a photocurrent for L-kynurenine (L-Kyn) that was 8.64-fold lower than that of D-Kyn, with a limit of detection (LOD) of 0.0074 nM for the L-Kyn, which was attributed to stronger affinity between L-Kyn and D-Se NPs. Noticeably, the chiral Se nanomembrane precisely distinguished L-Kyn in serum and cerebrospinal fluid samples from Alzheimer's disease patients and healthy subjects.

Ultrasmall Magneto-chiral Cobalt Hydroxide Nanoparticles Enable Dynamic Detection of Reactive Oxygen Species in Vivo.

Biological application of chiral nanoparticles (NPs) has aroused enormous levels of attention over recent years. Here, we synthesized magneto-chiral cobalt hydroxide (Co(OH)2) NPs that exhibited strong chiroptical and unique magnetic properties and applied these NPs to detect and monitor reactive oxygen species (ROS) in living cells and in vivo. Circular dichroism (CD) and magnetic resonance imaging (MRI) signals of the magneto-chiral Co(OH)2 NPs exhibited a wide intracellular ROS detection range from 0.673 to 612.971 pmol/106 cells with corresponding limits of detection (LOD) at 0.087 and 0.179 pmol/106 cells, far below that of currently available probes; the LOD for d-aspartic acid coated Co(OH)2 NPs (d-Co(OH)2 NPs) was 5.7 times lower than that for l-aspartic acid coated Co(OH)2 NPs (l-Co(OH)2 NPs) based on the CD signals. In addition, d-Co(OH)2 NPs also exhibited dynamic ROS monitoring ability. The high levels of selectivity and sensitivity to ROS in complex biological environments can be attributed to the Co2+ oxidation reaction on the surface of the NPs. Furthermore, magneto-chiral Co(OH)2 NPs were able to quantify the levels of ROS in living mice by fluorescence and MRI signals. Collectively, these results reveal that magneto-chiral Co(OH)2 NPs exhibit a remarkable ability to quantify ROS levels in living organisms, and could therefore provide new tools for exploring chiral nanomaterials as a potential biosensor to investigate biological events.

Quantitative zeptomolar imaging of miRNA cancer markers with nanoparticle assemblies.

Multiplexed detection of small noncoding RNAs responsible for posttranscriptional regulation of gene expression, known as miRNAs, is essential for understanding and controlling cell development. However, the lifetimes of miRNAs are short and their concentrations are low, which inhibits the development of miRNA-based methods, diagnostics, and treatment of many diseases. Here we show that DNA-bridged assemblies of gold nanorods with upconverting nanoparticles can simultaneously quantify two miRNA cancer markers, namely miR-21 and miR-200b. Energy upconversion in nanoparticles affords efficient excitation of fluorescent dyes via energy transfer in the superstructures with core-satellite geometry where gold nanorods are surrounded by upconverting nanoparticles. Spectral separation of the excitation beam and dye emission wavelengths enables drastic reduction of signal-to-noise ratio and the limit of detection to 3.2 zmol/ngRNA (0.11 amol or 6.5 × 104 copies) and 10.3 zmol/ngRNA (0.34 amol or 2.1 × 105 copies) for miR-21 and miR-200b, respectively. Zeptomolar sensitivity and analytical linearity with respect to miRNA concentration affords multiplexed detection and imaging of these markers, both in living cells and in vivo assays. These findings create a pathway for the creation of an miRNA toolbox for quantitative epigenetics and digital personalized medicine.

Enantiomeric NIR-II Emitting Rare-Earth-Doped Ag2 Se Nanoparticles with Differentiated In Vivo Imaging Efficiencies.

Here, chiral second near-infrared (NIR-II) emitting rare-earth doped silver selenide nanoparticles (R- or S-Ag2 Se:Nd/Yd/Er NPs) were fabricated, exhibiting circular dichroism peak at 850 nm and fluorescence peak at 1550 nm, with 145.7-fold enhanced intensity compared to the reported Ag2 Se NPs. Compared with S-Ag2 Se:Nd/Yd/Er NPs, imaging efficiency of R-Ag2 Se:Nd/Yd/Er NPs in living cells was significantly improved due to a higher cellular uptake rate and 927.7-fold higher affinity. Furthermore, R-Ag2 Se:Nd/Yd/Er NPs reached at the tumor 2-fold faster than S type of NPs in vivo. We discover that chirality leads to differences in the affinity between chiral Ag2 Se:Nd/Yd/Er NPs and cluster of differentiation 44 (CD44) onto the surface of murine mammary carcinoma cell to cause different in vivo imaging efficiency. These results reveal that chiral Ag2 Se:Nd/Yd/Er NPs have high photoluminescence intensity and high in vivo imaging efficiency reflecting wide applications in biomedical diagnosis.

Ultrasmall Copper (I) Sulfide Nanoparticles Prevent Hepatitis†B Virus Infection.

Hepatitis B virus (HBV) poses a severe threat to public health and social development. Here, we synthesized 4±0.5 nm copper (I) sulfide (Cu2 S) nanoparticles (NPs) with 46 mdeg chiroptical property at 530 nm to selectively cleavage HBV core antigen (HBcAg) and effectively blocked HBV assembly and prevented HBV infection both in vitro and in vivo under light at 808 nm. Experimental analysis showed that the chiral Cu2 S NPs specific bound with the functional domain from phenylalanine23 (F23 ) to leucine30 (L30 ) from HBcAg primary sequence and the cutting site was between amino acid residues F24 and proline25 (P25 ). Under excitation at 808 nm, the intracellular HBcAg concentration was reduced by 95 %, and in HBV transgenic mice, the levels of HBV surface antigen (HBsAg) and HBV DNA were decreased by 93 % and 86 %, respectively. Together, these results reveal the potential nanomedicine for HBV control and provide fresh tools for viral infection.

Improved Reactive Oxygen Species Generation by Chiral Co3 O4 Supraparticles under Electromagnetic Fields.

One of the most common methods to treat thromboembolism is the use of thrombolytic drugs to activate fibrinolytic protease. The aim of this treatment was to initiate the lysis of fibrin; however, there are many side-effects associated with this form of treatment. Herein, we fabricated chiral Co3 O4 supraparticles (SPs) with a g-factor of up to 0.02 at 550 nm and paramagnetic performance applied in the treatment of thromboembolism under an electromagnetic field (MF). In vitro experiments showed that d-SPs degraded blood clot within 8 hours under MF. Compared to l-SPs, d-SPs exhibited much stronger thrombolytic ability and effectively enhanced the survival rate of thrombosis model mice more than 70 % in the 25 d of observation. The results of mechanism study showed that under MF, the level of reactive oxygen species (ROS) produced by d-SPs were 1.5 times higher than that of l-SPs, which might be attributed to the chiral-induced spin selectivity effects.

Tetrahedron Probes for Ultrasensitive In Situ Detection of Telomerase and Surface Glycoprotein Activity in Living Cells.

In the present study, a tetrahedron probe with encoded internal reference nanoparticles (NPs) was self-assembled by a complementary nucleic acid aptamer for simultaneous ratiometric detection of telomerase (TE) and epithelial cell-adhesion molecule (EpCAM) in living cells. In the presence of a target, the dissociation of gold (Au) NPs, which was modified with corresponding tags, resulted in decreased surface-enhanced Raman scattering (SERS) signals. In addition, the ratios of Raman intensity at 1346 cm-1/1096 cm-1 (TE) and 1614 cm-1/1096 cm-1 (EpCAM) compared with the internal reference were demonstrated to quantify the level of TE and EpCAM, respectively, and can eliminate certain background noise. A good linear relationship was observed between them, and the linear range of TE and EpCAM in HeLa cells was 0.7 × 10-12 to 37.5 × 10-12 IU and 1.24 to 75.48 pg/mL with a limit of detection (LOD) of 7.6 × 10-16 IU and 0.53 pg/mL, respectively, which were consistent with the results of Raman confocal imaging. Meanwhile, the versatility and specificity of the developed probes were confirmed in cell lines. These results provide a reliable and ultrasensitive strategy for the in situ detection of biomarkers and a new method for SERS-based tetrahedrons in the early diagnosis of cancer.

Chiral Cux Coy S Nanoparticles under Magnetic Field and NIR Light to Eliminate Senescent Cells.

In the present study, chiral Cux Coy S nanoparticles (NPs) were developed to selectively induce apoptosis of senescent cells using both an alternating magnetic field (AMF) and near infrared (NIR) photon illumination. The chiral effects on living cells were investigated, and d-Cux Coy S NPs showed about 2.5 times higher of internalized ability than l-NPs. By modifying beta 2 macroglobulin (MG), senescent cells were effectively eliminated by d-Cux Coy S NPs without damaging the activities of normal cells under AMF and photon illumination. Compared to the individual application of NIR illumination and AMF, their synergistic effect induced the production of caspase-3 with a much shorter treatment time and higher efficiency due to the more serious photon-induced cellular redox and mechanical damage of cellular skeleton. Moreover, the developed strategy was successfully used to remove senescent cells in vivo. This study developed a controllable way of regulating cell activities using chiral NPs, which will provide a valuable way for treating diseases and promoting health.

Mitochondria-Targeting Plasmonic Spiky Nanorods Increase the Elimination of Aging Cells in Vivo.

Cellular senescence is stress-induced, irreversible growth arrest, and is thought to impair tissue function. The clearance of senescent cells can delay the features of senescence. Herein, we report the development of plasmonic core-shell spiky nanorods (CSNRs) surface-modified with an anti-beta-2-microglobulin (aB2MG) antibody and triphenylphosphonium (TPP), to target the mitochondria in senescent cells. aB2MG-TPP@CSNRs irradiated with near-infrared (NIR) light selectively caused mitochondrial damage and apoptosis of senescent cells with relatively low NIR light power, and the ability of CSNRs to activate and amplify the immune response in vitro and in vivo was discovered. The photo-induced generation of reactive oxygen species (ROS) resulted in senescent-cell apoptosis and immune adjuvant effect by CSNRs accelerated the clearance of senescent cells in mice. This study opens the way for the use of precisely regulated plasmonic nanostructures for immune adjuvant and photo-induced apoptosis for age-related senescence.

Light-Induced Chiral Iron Copper Selenide Nanoparticles Prevent ß-Amyloidopathy In†Vivo.

The accumulation and deposition of ß-amyloid (Aß) plaques in the brain is considered a potential pathogenic mechanism underlying Alzheimer's disease (AD). Chiral l/d-Fex Cuy Se nanoparticles (NPs) were fabricated that interfer with the self-assembly of Aß42 monomers and trigger the Aß42 fibrils in dense structures to become looser monomers under 808 nm near-infrared (NIR) illumination. d-Fex Cuy Se NPs have a much higher affinity for Aß42 fibrils than l-Fex Cuy Se NPs and chiral Cu2-x Se NPs. The chiral Fex Cuy Se NPs also generate more reactive oxygen species (ROS) than chiral Cu2-x Se NPs under NIR-light irradiation. In living MN9D cells, d-NPs attenuate the adhesion of Aß42 to membranes and neuron loss after NIR treatment within 10 min without the photothermal effect. In-vivo experiments showed that d-Fex Cuy Se NPs provide an efficient protection against neuronal damage induced by the deposition of Aß42 and alleviate symptoms in a mouse model of AD, leading to the recovery of cognitive competence.

Chiral Molecule-mediated Porous Cu xO Nanoparticle Clusters with Antioxidation Activity for Ameliorating Parkinson's Disease.

Reactive oxygen species (ROS)-mediated mitochondrial dysfunction is one of the major pathological mechanisms of Parkinson's disease. Using inorganic nanomaterials to scavenge ROS has drawn significant interest and can prevent ROS-mediated neurological disorders. We prepared uniform Cu xO nanoparticle clusters (NCs) with an average size of 65 ± 7 nm, using phenylalanine (Phe) as the structure-directing agent. These Cu xO NCs functionally mimicked the activities of peroxidase, superoxide dismutase, catalase, and glutathione peroxidase. Because they eliminated ROS, the Cu xO NCs inhibited neurotoxicity in a cellular model of Parkinson's disease and rescued the memory loss of mice with Parkinson's disease. The biocompatibility and multiple enzyme-mimicking activities of Cu xO NCs offer new opportunities for the application of NCs in biomedicine, biosensing, and biocatalysis.

Chiral Core-Shell Upconversion Nanoparticle@MOF Nanoassemblies for Quantification and Bioimaging of Reactive Oxygen Species in Vivo.

In this study, a hybrid nanoassembly consisting of an upconversion nanoparticle (UCNP) core and a zeolitic imidazolate framework-8 (ZIF) shell encapsulated with chiral NiSx NPs (denoted as UCNP@ZIF-NiSx) were fabricated. The UCNP@ZIF-NiSx nanoassemblies showed an intense circular dichroism (CD) signal at 440 and 530 nm, whereas the upconversion luminescence (UCL) signal of the UCNPs at 540 nm were quenched by NiSx NPs and the UCL signal at 660 nm was almost unchanged. By taking advantage of the chiral-optical and fluorescent signals, the dual mode nanoassemblies can be used for quantitively monitoring reactive oxygen species (ROS), with hydrogen peroxide (H2O2) as the proof-of-concept target in living cells. The experimental results revealed that UCNP@ZIF-NiSx has been changed into UCNP@ZIF with degradation of NiSx during the detection process. Noticeably, quantitative and selective detection of ROS was successfully carried out in vivo. This strategy highlights the potential of chiral nanoassemblies for ROS detection, which opens up a new avenue to develop the toolbox of chiral nanomaterials for biomedical and biological analysis.

Circularly Polarized Light Triggers Biosensing Based on Chiral Assemblies.

Chiral assemblies have attracted great interest because of their many potential applications, such as in chiral sensing, asymmetric catalysis, and optical devices. Here, by using specific DNAzymes, a chiral core-satellite assembly consisting of a DNAzyme-driven spiny nanorod dimer core and upconversion nanoparticle (UCNP) satellite was constructed. The chirality of this assembly originates from the geometry chirality. This chiral assembly can be used as a photothermally activated probe for the simultaneous detection of multiple analytes in living cells. Under illumination with 980 nm left circularly polarized (LCP) light, this probe was used to quantify and visualize intracellular metal ions.

Chiral Semiconductor Nanoparticles for Protein Catalysis and Profiling.

In this study, via a simple one-step method, chiral copper sulfide quantum dots (d/l-QDs) were prepared using d-/l-penicillamine (d-/l-Pen). The anisotropy factor of d/l-QDs was as high as 0.01. The d/l-QDs can be used as photocatalysts to cleave proteins. Notably, the l-QDs displayed the highest catalytic performance under left-circularly polarized light irradiation. Mechanistic investigations indicate the generation of hydroxyl radicals as the reactive species that cause the cutting of proteins.

Porous Cux Coy S Supraparticles for In†Vivo Telomerase Imaging and Reactive Oxygen Species Generation.

In this study, we successfully synthesized Cux Coy S supraparticles (SPs) on the nanoscale featuring multiple pores inside and strong absorption from 400 to 900 nm. Porous Cux Coy S SPs produced the highest reactive oxygen species (ROS) yield (1.39) when illuminated with near-infrared (NIR) light. Furthermore, we demonstrated that Cux Coy S SPs could be used to identify cancer cells through intracellular telomerase-responsive fluorescence (FL) imaging in living cells. Because the Cux Coy S SPs were associated with telomerase-responsive bioimaging and high ROS production, they can be efficiently used in the diagnosis and therapy of tumors with high selectivity and excellent therapeutic effects in vivo. This study provides a new vision for the creation of multifunctional SPs, which can be used as cellular sensors and control tools for pathologies across a broad range of biological systems.

Self-Assembled Gold Arrays That Allow Rectification by Nanoscale Selectivity.

The deposition of a monolayer nanoarray on the surface of a micrometer-thick substrate is demonstrated, producing rectification characteristics at the nanoscale. The experimental results show that the heterogeneity of the structure and the charge density are the two key factors affecting rectification, which was confirmed with molecular dynamic (MD) and finite element simulations. Moreover, by altering the asymmetric electrolyte environment, the fabricated heterogeneous membrane can be used in energy conversion. This study provides insights into the mechanism underlying the generation of rectification and related factors, providing a theoretical basis for the characteristics of rectification.