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This is an early access version, the complete PDF, HTML, and XML versions will be available soon.
Article

Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma

by
Laura Di Magno
1,†,
Federica Rinaldi
2,†,
Luca Campea
1,
Giorgia Della Rocca
1,
Jacopo Forte
3,
Eleonora D’Intino
2,
Sara Cairoli
4,
Bianca Maria Goffredo
4,
Maria Carafa
2,
Elena Del Favero
5,
Carlotta Marianecci
2,* and
Gianluca Canettieri
1,6,*
1
Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy
2
Department of Drug Chemistry and Technology, Sapienza University of Rome, Piazzale A. Moro 5, 00185 Rome, Italy
3
Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Catholic University of Sacred Heart, Largo Francesco Vito 1, 00168 Rome, Italy
4
Division of Metabolic Diseases and Drug Biology, Bambino Gesù Children’s Hospital, IRCCS, Via Ferdinando Baldelli 38, 00146 Rome, Italy
5
Department of Medical Biotechnology and Translational Medicine, University of Milan, Viale F.lli Cervi 93, 20054 Segrate, Italy
6
Institute Pasteur Italia, Fondazione Cenci-Bolognetti, Viale Regina Elena 291, 00161 Rome, Italy
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Nanomaterials 2026, 16(9), 566; https://doi.org/10.3390/nano16090566
Submission received: 26 February 2026 / Revised: 17 April 2026 / Accepted: 29 April 2026 / Published: 4 May 2026
(This article belongs to the Special Issue New Progress in Targeted Delivery of Nanocarriers)
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Abstract

Medulloblastoma (MB) is the most frequent brain malignancy in children, frequently driven by deregulated Sonic Hedgehog (SHH) signaling. We previously identified the antidiabetic drug phenformin (Phen) as a potent Gli1 inhibitor that suppresses SHH-subtype MB growth. Despite its efficacy, systemic administration of Phen is limited by its potential to induce lactic acidosis, primarily through the suppression of hepatic gluconeogenesis. Here, we provide proof-of-concept that phospholipid (liposomes) and non-phospholipid (niosomes) vesicles (<200 nm) can be used to deliver phenformin selectively. Our results show that these vesicle-based delivery systems efficiently entrap Phen (around 50%) and release it into SHH MB cells, reducing proliferation and activating energy stress responses at higher doses. Furthermore, treated cells exhibit marked downregulation of SHH target genes Gli1 and Ptch1. In vivo, phenformin-loaded nanocarriers selectively increased drug accumulation in cerebellar tumors while minimizing systemic and hepatic exposure. Notably, niosomes demonstrated superior brain tumor targeting compared to free drug or liposome administration, as reflected by higher intratumoral concentrations of Phen compared to free drug or liposome administration. Consistent with this targeted delivery, we observed a substantial decline in intratumoral Gli1 and Ptch1 expression, confirming effective SHH pathway modulation. Together, these findings propose a promising nanotechnology-based method to improve phenformin therapeutic index in SHH MB by enhancing tumor specificity and reducing systemic toxicity.
Keywords: Hedgehog; phenformin; niosomes; medulloblastoma; drug targeting; biodistribution; nanocarriers; liposomes; brain drug delivery; blood-brain barrier Hedgehog; phenformin; niosomes; medulloblastoma; drug targeting; biodistribution; nanocarriers; liposomes; brain drug delivery; blood-brain barrier
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MDPI and ACS Style

Di Magno, L.; Rinaldi, F.; Campea, L.; Della Rocca, G.; Forte, J.; D’Intino, E.; Cairoli, S.; Goffredo, B.M.; Carafa, M.; Del Favero, E.; et al. Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma. Nanomaterials 2026, 16, 566. https://doi.org/10.3390/nano16090566

AMA Style

Di Magno L, Rinaldi F, Campea L, Della Rocca G, Forte J, D’Intino E, Cairoli S, Goffredo BM, Carafa M, Del Favero E, et al. Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma. Nanomaterials. 2026; 16(9):566. https://doi.org/10.3390/nano16090566

Chicago/Turabian Style

Di Magno, Laura, Federica Rinaldi, Luca Campea, Giorgia Della Rocca, Jacopo Forte, Eleonora D’Intino, Sara Cairoli, Bianca Maria Goffredo, Maria Carafa, Elena Del Favero, and et al. 2026. "Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma" Nanomaterials 16, no. 9: 566. https://doi.org/10.3390/nano16090566

APA Style

Di Magno, L., Rinaldi, F., Campea, L., Della Rocca, G., Forte, J., D’Intino, E., Cairoli, S., Goffredo, B. M., Carafa, M., Del Favero, E., Marianecci, C., & Canettieri, G. (2026). Brain-Targeted Delivery of Phenformin Using Phospholipid and Non-Phospholipid Vesicles for SHH Medulloblastoma. Nanomaterials, 16(9), 566. https://doi.org/10.3390/nano16090566

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