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  3. A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy

A first-in-class non-cytotoxic nanocarrier based on a recombinant human ferritin boosts targeted therapy, chemotherapy and immunotherapy

  • Int J Biol Macromol. 2025 May;309(Pt 1):142843. doi: 10.1016/j.ijbiomac.2025.142843.
Giada Tisci 1,  Lenka Rajsiglova 2,  Sandra Bibbo 3,  Giovanna Ziccheddu 4,  Elena Ricciardi 4,  Elisabetta Falvo 5,  Vincenzo De Laurenzi 3,  Gianluca Sala 6,  Emily Capone 3,  Gianni Colotti 5,  Alessandro Arcovito 7,  Noah Giacon 8,  Peter Makovický 9,  Leonid Sushytskyi 10,  Pavol Lukac 2,  Luca Vannucci 11,  Patrizio Giacomini 12,  Pierpaolo Ceci 13
Affiliations

Affiliations

  • 1 Department of Biochemical Sciences, Sapienza University, Rome, Italy.
  • 2 Laboratory of Immunotherapy, Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic; Department of Cell Biology, Faculty of Science, Charles University, Prague, Czech Republic.
  • 3 Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), Italy.
  • 4 Translational Oncology Unit, IRCCS National Cancer Institute Regina Elena, Via Elio Chianesi 53, Rome, Italy.
  • 5 Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy.
  • 6 Department of Innovative Technologies in Medicine & Dentistry, University of Chieti-Pescara, Chieti, Italy; Center for Advanced Studies and Technology (CAST), Italy. Electronic address: g.sala@unich.it.
  • 7 Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo F. Vito 1, Rome, Italy; Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy.
  • 8 Dipartimento di Scienze Biotecnologiche di Base, Cliniche Intensivologiche e Perioperatorie, Università Cattolica del Sacro Cuore, Largo F. Vito 1, Rome, Italy.
  • 9 Institute of Histology and Embryology, Faculty of Medicine, University of Ostrava, Syllabova 19, Ostrava-Vítkovice, Czech Republic.
  • 10 Laboratory of Immunotherapy, Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic; Department of Carbohydrates and Cereals, Faculty of Food and Biochemical Technology, University of Chemistry and Technology in Prague, Technická 5, 166 28 Prague, Czech Republic.
  • 11 Laboratory of Immunotherapy, Institute of Microbiology, Czech Academy of Sciences, Prague, Czech Republic.
  • 12 UOSD Medicina di Precisione in Senologia, Fondazione Policlinico Universitario "A. Gemelli", IRCCS, Largo Agostino Gemelli 8, Rome, Italy.
  • 13 Institute of Molecular Biology and Pathology, Italian National Research Council IBPM-CNR, Rome, Italy; Thena Biotech, Latina, Italy. Electronic address: pierpaolo.ceci@cnr.it.
PMID: 40187454 DOI: 10.1016/j.ijbiomac.2025.142843
Abstract

To address the challenge of drug accumulation and penetration at the tumor site(s), herein we describe a first-in-class nanocarrier containing 24 copies each of two bioactive peptides (BAPs) genetically fused in frame to the 24 N-termini of a human ferritin H-type construct, named THE-10. The two BAPs are specific for PD-L1 and Integrin αVβ3/αvβ5 plus Neuropilin (iRGD) respectively, conferring immune checkpoint blockade and drug-internalization properties. In turn, the THE-10 backbone brings 48 BAPs contiguous for synergism, prolonged blood half-life, and release into the tumor microenvironment upon conditional cleavage of a metalloprotease-sensitive site. Predicted THE-10 multitasking activity was experimentally supported as follows. Size-exclusion chromatography and surface plasmon resonance demonstrated BAP cleavage/release and receptor binding (nanomolar KD). Live-cell/time-lapse imaging demonstrated 4-fold-increased internalization of naked therapeutic antibodies, mirrored by enhanced cytotoxicity of the corresponding Antibody-Drug Conjugate. Slight antitumor effects were observed in vivo by treating immune checkpoint-sensitive syngeneic mouse colorectal model with THE-10 alone. Drug boosting was instead considerable on colorectal and pancreatic tumor allografts when THE-10 was co-administered with both small and large chemotherapeutic agents, outperforming the original iRGD cyclic peptide. Thus, THE-10 may enhance target therapy, chemotherapy and immunotherapy altogether, e.g. it candidates as a multitasking, all-round, antineoplastic therapy booster.

Keywords

Human ferritin nanocarrier; Peptide grafting; cancer therapy booster.

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