Supercharged ferritin nanocages enable universal cytosolic protein delivery

  • Nat Commun. 2026 Jun 9. doi: 10.1038/s41467-026-74247-x.
Dingkang Liu  #  1  2 ,  Hong Luo  #  1 ,  Qingzhou Lu  #  1 ,  Lichao Yu  1 ,  Minjiang Chen  3 ,  Wenbing Yao  1 ,  Pan Hu  2 ,  Lubin Liu  2 ,  Wei Liu  4 ,  Xiangdong Gao  5 ,  Jiansong Ji  6 ,  Jun Yin  7  8
Affiliations
  • 1. Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China.
  • 2. Department of Obstetrics and Gynecology, Women and Children's Hospital of Chongqing Medical University, Chongqing, China.
  • 3. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China.
  • 4. Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. [email protected].
  • 5. Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. [email protected].
  • 6. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China. [email protected].
  • 7. Jiangsu Key Laboratory of Druggability of Biopharmaceuticals and State Key Laboratory of Natural Medicines, School of Life Science and Technology, China Pharmaceutical University, Nanjing, China. [email protected].
  • 8. Zhejiang Key Laboratory of Imaging and Interventional Medicine, Zhejiang Engineering Research Center of Interventional Medicine Engineering and Biotechnology, The Fifth Affiliated Hospital of Wenzhou Medical University, Lishui, China. [email protected].
  • # Contributed equally.
PMID: 42259798 DOI: 10.1038/s41467-026-74247-x
Abstract

Efficient intracellular protein delivery represents an essential prerequisite for protein-based biotechnologies and therapeutics targeting intracellular components. However, this process is limited by multiple factors, including nonspecific protein binding, insufficient cellular uptake, inefficient endosomal escape, and inadequate cytosolic protein release. Here we show that by engineering fully recombinant supercharged protein nanocages, we achieve exceptionally high cellular uptake using a strategy we term 'supercharged interface engineering'. By incorporating unnatural Amino acids bearing phenylboronic acid groups, we develop a representative protein nanocage, pFn + . Simply mixing pFn+ with protein cargoes forms a noncovalent complex possessing enhanced cellular uptake efficiency, robust endosomal escape capability, and excellent biocompatibility. Notably, this system successfully delivers functional gene-editing tools and therapeutic antibodies in female mouse models. These findings indicate that pFn+ represents a promising platform for enhancing the cytosolic delivery of protein cargoes. Moreover, the proposed supercharged interface engineering strategy is valuable for advancing next-generation intracellular protein delivery systems.

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