Dual modified ferritin nanocages for tumor-targeted and microenvironment-responsive drug delivery

  • Int J Biol Macromol. 2025 Feb 4:140694. doi: 10.1016/j.ijbiomac.2025.140694.
Hanlin Li  1 ,  Yuhan Qu  2 ,  Zhanzhi Guo  2 ,  Dan Chen  3 ,  Longguang Jiang  1 ,  Peng Xu  2 ,  Mingdong Huang  4 ,  Cai Yuan  5
Affiliations
  • 1. College of Chemistry, Fuzhou University, Fujian 350108, China.
  • 2. College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China.
  • 3. Department of Cardiology, Heart Center of Fujian Province, Fujian Medical University Union Hospital, Fuzhou, Fujian 350001, China.
  • 4. College of Chemistry, Fuzhou University, Fujian 350108, China. Electronic address: [email protected].
  • 5. College of Biological Science and Engineering, Fuzhou University, Fuzhou, Fujian 350108, China. Electronic address: [email protected].
PMID: 39914543 DOI: 10.1016/j.ijbiomac.2025.140694
Abstract

Human heavy-chain ferritin (HFn) possesses a stable and uniform cage-like structure, tumor-targeting properties, self-assembly capabilities, and biocompatibility, rendering it an ideal candidate for drug delivery. Here, we developed a dual modified HFn-based nanocage (DFn) that targets the urokinase-type plasminogen activator receptor (uPAR) and, at the same time, is responsive to the tumor microenvironment for controlled extracellular drug release. This DFn was used to co-encapsulate a Photosensitizer (CPZ) and a hypoxia-activated prodrug (TPZ), creating the multifunctional nanoparticles C/T@DFn. In vitro cellular assays demonstrated that C/T@DFn significantly outperformed both unmodified HFn-based nanoparticles and its counterpart without the uPAR-targeting motif in inhibiting tumor cell survival, proliferation, and migration, and showed enhanced tumor cell spheroids penetration. In vivo studies further demonstrated the improved tumor-specific accumulation and antitumor efficacy of the loaded cargo in the DFn nanocages in comparison with wild-type HFn. This improved therapeutic effect is achieved through receptor-mediated targeting and tumor microenvironment-responsive release of the cargo from the DFn nanocages, resulting in synergistic action of CPZ and TPZ within the tumor tissue. Overall, this study introduces an ideal ferritin-based nanoplatform for the efficient co-delivery of therapeutic agents, offering a promising strategy for targeted tumor therapy.

Keywords
Antitumor; Ferritin nanocage; uPAR-targeting.
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