Zhang Tao, Lei Tingyun, Yan Ruojin, Zhou Bo, Fan Chunmei, Zhao Yanyan, Yao Shasha, Pan Haihua, Chen Yangwu, Wu Bingbing, Yang Yuwei, Hu Lijuan, Gu Shen, Chen Xiaoyi, Bao Fangyuan, Li Yu, Xie Hanqi, Tang Ruikang, Chen Xiao, Yin Zi
Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, and Department of Orthopedic Surgery of Sir Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, 310058, PR China.
Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, Hangzhou, 310058, PR China.
Bioact Mater. 2022 Mar 26;18:199-212. doi: 10.1016/j.bioactmat.2022.03.026. eCollection 2022 Dec.
Although ultra-small nanoclusters (USNCs, < 2 nm) have immense application capabilities in biomedicine, the investigation on body-wide organ responses towards USNCs is scant. Here, applying a novel strategy of single-cell mass cytometry combined with Nano Genome Atlas of multi-tissues, we systematically evaluate the interactions between the host and calcium phosphate (CaP) USNCs at the organism level. Combining single-cell mass cytometry, and magnetic luminex assay results, we identify dynamic immune responses to CaP USNCs at the single cell resolution. The innate immune is initially activated and followed by adaptive immune activation, as evidenced by dynamic immune cells proportions. Furthermore, using Nano Genome Atlas of multi-tissues, we uncover CaP USNCs induce stronger activation of the immune responses in the cartilage and subchondral bone among the five local tissues while promote metabolic activities in the liver and kidney. Moreover, based on the immunological response profiles, histological evaluation of major organs and local tissue, and a body-wide transcriptomics, we demonstrate that CaP USNCs are not more hazardous than the Food and Drug Administration-approved CaP nanoparticles after 14 days of injection. Our findings provide valuable information on the future clinical applications of USNCs and introduce an innovative strategy to decipher the whole body response to implants.
尽管超小纳米团簇（USNCs，<2纳米）在生物医学中具有巨大的应用潜力，但目前关于全身各器官对USNCs反应的研究却很少。在此，我们应用单细胞质谱流式细胞术与多组织纳米基因组图谱相结合的新策略，在生物体水平上系统地评估宿主与磷酸钙（CaP）USNCs之间的相互作用。结合单细胞质谱流式细胞术和磁珠免疫分析结果，我们在单细胞分辨率下确定了对CaP USNCs的动态免疫反应。动态免疫细胞比例表明，先天免疫最初被激活，随后适应性免疫被激活。此外，利用多组织纳米基因组图谱，我们发现CaP USNCs在五个局部组织中诱导软骨和软骨下骨的免疫反应更强，同时促进肝脏和肾脏的代谢活动。此外，基于免疫反应谱、主要器官和局部组织的组织学评估以及全身转录组学，我们证明在注射14天后，CaP USNCs并不比美国食品药品监督管理局批准的CaP纳米颗粒更具危害性。我们的研究结果为USNCs未来的临床应用提供了有价值的信息，并引入了一种创新策略来解读全身对植入物的反应。
