Abstract
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 nanoparticles1,2,3,4; however, little is known about their effects on complex biochemical networks5,6. Intermolecular interactions of biological molecules and inorganic nanoparticles show some commonalities7,8,9, 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.
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Data availability
Source data for Figs. 3, 4 and Extended Data Figs. 1, 2 are provided with this paper. The data supporting the findings of this study are available within the paper and its Supplementary Information files. Source data are provided with this paper.
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Acknowledgements
This work was financially supported by the National Natural Science Foundation of China (21925402, 32071400, 21977038, 92156003), Natural Science Foundation of Jiangsu Province (BK20212014), and Young Elite Scientist Sponsorship Program by China Association for Science and Technology (CAST) (2019QNRC001). N.A.K thanks the US National Science Foundation (NSF) (grants 1463474 and 1566460) for support. A.F.M. thanks the Brazilian Ministério da Educação (MEC)/Tutorial Education Programme (PET) for a fellowship and Conselho Nacional de Desenvolvimento Cientifíco e Tecnólogico (CNPq) for a research fellowship (311353/2019-3). We thank the Brazilian funding agencies Coordenação de Aperfeiçoamento de Pessoal de Nível Superio (CAPES), CNPq, and Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) (processes 2012/15147-4 and 2013/07296-2) for financial support; and the high-performance computer (HPC) resources provided by the SDumont supercomputer at the National Laboratory for Scientific Computing (Laboratório Nacional de Computação Científica (LNCC)/Ministério da Ciência, Tecnologia e Inovações (MCTI), Brazil; http://sdumont.lncc.br) and by the Cloud@UFSCar.
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H.K., N.A.K. and C.X. conceived the project and planned the experiments. L.X., X. Wang, C.H., S.L. and X. Wu fabricated the chiral nanoparticles. L.X., W.W., M.S., A.Q., M.L. and X.G. carried out immunological experiments. X. Wang and X.G. measured the affinity constant between chiral nanoparticles and receptors. L.X., M.S., A.Q. and M.L. carried out the inflammasome experiments. W.J.C. carried out electromagnetic modelling and simulation. J.-Y.K. calculated the chirality measures. F.M.C., W.R.G., A.L.B. and A.F.D. carried out electrodynamics calculations. L.X., H.K., N.A.K. and C.X. conceptualized the work, wrote the manuscript, and compiled figures, with discussion of results and feedback on the manuscript from all authors.
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Extended data figures and tables
Extended Data Fig. 1 Chiral nanoparticles are taken up by human BMDCs and activate inflammasomes.
a, Flow-cytometry data for human BMDCs after being treated with PBS, anti-EMR1 antibody (30 μg ml−1, blocking EMR1), anti-CD97 antibody (20 μg ml−1, blocking CD97), or both anti-EMR1 antibody (30 μg ml−1) and anti-CD97 antibody (20 μg ml−1) (blocking both CD97 and EMR1) and then incubated with l-P+ NP(2 nM) or d-P− NP (2 nM) for 8 h. b, Confocal imaging of human BMDCs incubated with 2 μg ml−1 MPL, 20 μg ml−1 OVA and 2 nM l-P+ NP with various incubation times up to 4 h. Blue, DAPI; red, CD97–Cy5; green: l-P+ NP–Cy3. Scale bar, 10 μm. c, Confocal imaging of NLRP3 inflammasome activation in mouse BMDCs after incubation with PBS, MPL plus OVA, l-P+ NP + MPL + OVA, l-P+ NP + MPL + OVA + MCC950 (NLRP3 inhibitor), l-P+ NP + MPL + OVA + amiodarone (K+-channel inhibitor), l-P+ NP + MPL + OVA + KCl (K+-efflux inhibitor), l-P+ NP + MPL + OVA + dynasore (dynamin inhibitor), l-P+ NP + MPL + OVA + chlorpromazine (clathrin inhibitor), l-P+ NP + MPL + OVA + CA-074-Me (cathepsin B inhibitor), l-P+ NP + MPL + OVA + cytochalasin D (phagocytosis inhibitor), l-P+ NP + MPL + OVA + NAC (inhibitor of reactive oxygen species, ROS) and l-P+ NP + MPL + OVA + nocodazole (microtubule inhibitor) for 12 h. Blue, DAPI; red, caspase-1; green, NLRP3. Scale bar, 20 μm. Data are mean ± s.d. (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001, analysed by Student’s t-test.
Extended Data Fig. 2 Chirality-dependent efficiency of vaccination in mice.
a, IL-1β concentration in the culture medium of mouse BMDCs after incubation with chiral nanoparticles of different g-factors, measured by ELISA. b, Expression of NLRP3 in wild-type mice after treatment with chiral nanoparticles of different g-factors, detected by flow cytometry. c–f, Influenza vaccination. C57BL/6 mice (n = 5) were immunized with H9N2 influenza vaccine and the indicated adjuvants, including MPL, alum + MPL, d-P− NP + MPL, l-P+ NP + MPL, NS-d-CYP + MPL, or NS-l-CYP + MPL. c, The serum of the mice was collected to measure vaccine-specific antibody titres. d–f, IFN-γ-secreting CD8+ T cells (d), IFN-γ-secreting CD4+ T cells (e) and IL-4-secreting CD4+ T cells (f) in the spleen were measured by flow cytometry 7 days after immunization. Data are means ± s.d. (n = 5). *P < 0.05, **P < 0.01, ***P < 0.001, analysed by Student’s t-test.
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Xu, L., Wang, X., Wang, W. et al. Enantiomer-dependent immunological response to chiral nanoparticles. Nature 601, 366–373 (2022). https://doi.org/10.1038/s41586-021-04243-2
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DOI: https://doi.org/10.1038/s41586-021-04243-2
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