Self‐Assembly of Heterogeneous Ferritin Nanocages for Tumor Uptake and Penetration

• Published in: Advanced science 2024-05, Vol.11 (17), p.e2309271-n/a
• Main Authors: Liu, Qiqi, Wang, Chunyu, Zhu, Mingsheng, Liu, Jinming, Duan, Qiannan, Midgley, Adam C., Liu, Ruming, Jiang, Bing, Kong, Deling, Chen, Quan, Zhuang, Jie, Huang, Xinglu
• Format: Article
• Language: English
• Subjects: Binding sites; Chromatography; E coli; ferritin; heterogeneous nanostructures; Ligands; Nanoparticles; Plasmids; protein nanocages; Proteins; Reproducibility; self‐assembly; Synthetic biology; tumor; Tumors
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202309271

Well‐defined nanostructures are crucial for precisely understanding nano‐bio interactions. However, nanoparticles (NPs) fabricated through conventional synthesis approaches often lack poor controllability and reproducibility. Herein, a synthetic biology‐based strategy is introduced to fabricate uniformly reproducible protein‐based NPs, achieving precise control over heterogeneous components of the NPs. Specifically, a ferritin assembly toolbox system is developed that enables intracellular assembly of ferritin subunits/variants in Escherichia coli. Using this strategy, a proof‐of‐concept study is provided to explore the interplay between ligand density of NPs and their tumor targets/penetration. Various ferritin hybrid nanocages (FHn) containing human ferritin heavy chains (FH) and light chains are accurately assembled, leveraging their intrinsic binding with tumor cells and prolonged circulation time in blood, respectively. Further studies reveal that tumor cell uptake is FH density‐dependent through active binding with transferrin receptor 1, whereas in vivo tumor accumulation and tissue penetration are found to be correlated to heterogeneous assembly of FHn and vascular permeability of tumors. Densities of 3.7 FH/100 nm2 on the nanoparticle surface exhibit the highest degree of tumor accumulation and penetration, particularly in tumors with high permeability compared to those with low permeability. This study underscores the significance of nanoparticle heterogeneity in determining particle fate in biological systems. Creating heterogeneous nanoparticles with controllability and reproducibility remains challenging using conventional synthesis approaches. Herein, a synthetic biology‐based approach is introduced that enables the creation of a highly uniform and controllable living nanosystem, allowing for the tailoring of heterogeneous ferritin nanocages through spontaneous assembly. A proof‐of‐concept study illustrates the significant impact of nanoparticle heterogeneity on both tumor uptake and penetration.