Massimiliano Caiazzo

Dr. Massimiliano Caiazzo

Massimiliano Caiazzo started his studies in Naples (Italy) at the Institute of Genetics and Biophysics CNR “A. Buzzati-Traverso” and at CE.IN.GE. Biotecnologie Avanzate where he was involved in the study of the transcription factors that drive induction and differentiation of midbrain dopamine neurons. Subsequently he gained experience at hospital San Raffaele in Milano (Italy)  where he pioneered studies on the generation of dopamine neurons by direct cell reprogramming. He eventually completed his training at EPFL in the Laboratory of Stem Cell and Bioengineering where he combined the use of 3D hydrogels with cell reprogramming and organogenesis.

In 2016 he started his own research lines  at Utrecht University as assistant professor to focus on brain-targeted cell therapies.

Research

Massimiliano Caiazzo research is focused on regenerative medicine in the field of neurobiology. He aims to combine non-viral delivery technologies and RNA therapeutics to develop  innovative therapies for brain diseases. The main focus of his projects is the development of brain-targeting  technologies, implementing mRNA-lipid nanoparticles (LNPs), nanobodies and engineered immune cells.  

The three main ongoing projects in Caiazzo team are the following:

Generation of brain-targeting therapies mediated by HB-EGF nanobody transcytosis through the blood-brain barrier

Receptor-mediated transcytosis (RMT) is a targeted vesicular transport mechanism of brain endothelial cells that can be employed to specifically transport large therapeutic molecules into the brain. ProHB-EGF is the transmembrane precursor of the heparin-binding EGF-like growth factor (HB-EGF) present on the intraluminal side of the brain endothelial cells where and is known to exert its signaling also via RMT. Therefore, HB-EGF targeted nanobodies are promising tools to shuttle therapeutics through the blood-brain barrier (Qiu et al., 2025).  To date we are focusing on the implementation of HB-EGF nanobodies to generate drug-conjugate approaches for brain cancer.

Receptor mediated transcytosis across the BBB

Engineered LNPs for brain-targeting approaches.

LNPs are a powerful tool to deliver RNA therapeutics but their in vivo natural tropism is mainly targeting the liver. In order to drive mRNA-LNPs towards the brain, several targeting moieties can be implemented to steer their tropism. Specifically, we are focusing on the generation of mRNA-LNPs engineered with nanobodies that can perform RMT through the blood-brain barrier, and the combinations of them with corona proteins that opsonize LNPs in the blood stream. These engineered LNPs will be also tested for the implementation of neurogenic transcription factors (TFs) as potential neuroregenerative agents (Redi et al., 2025).

Generation of reprogrammed NK cells for cancer immunotherapy

NK cell-based immunotherapy is a promising avenue for several diseases, including solid tumors (Douka et al. 2025). We have previously shown that mRNA-LNPs are an elective tool to engineer NK cells avoiding viral vector drawbacks (Douka et al., 2023). To date, we are working on the generation of reprogrammed NK cells via the modulation of activating receptors (i.e. CD16) or via the expression of chimeric antigen receptors (CAR) in order to improve their killing activity and steer their in vivo targeting. These strategies could eventually generate innovative tools to treat brain cancer such as glioblastoma and brain metastatic tumours.

Selected publications

  1. Qiu B., Pompe S., Xenaki K.T., di Maggio A., van Bergen en Henegouwen P.M.P, Oliveira S., Mastrobattista E., Caiazzo M. Generation of a perfusable three-dimensional human neurovascular chip to model brain drug delivery and immune extravasation. Journal of Controlled Release. 2025, 387:114257. doi: 10.1016/j.jconrel.2025.114257.
  2. Qiu B., Pompe S., Xenaki K.T., Di Maggio A., Belinchón Moreno C., van Bergen en Henegouwen P.M.P., Mastrobattista E., Oliveira S., Caiazzo M. Nanobody targeting membrane-anchored Heparin-binding EGF- like growth factor penetrates blood-brain barrier via receptor-mediated transcytosis. Journal of Controlled Release, 2025;18;383:113852. doi: 10.1016/j.jconrel.2025.113852.
  3. Redi G., Del Piano F., Paladino M., Cappellini S., den Breejen A., Fens H.A.M., Caiazzo M. Delivery systems in neuronal direct cell reprogramming. Cellular Reprogramming 2025, doi: 10.1089/cell.2025.0008
  4. Douka S., Brandenburg L.E., Casadidio C., Walther J., Bonetto Moreno Garcia B., Spanholtz J., Raimo M., Hennink W.E., Mastrobattista E., Caiazzo M. Lipid nanoparticle-mediated messenger RNA delivery for ex vivo engineering of natural killer cells. Journal of Controlled Release 2023, 361:455-469. doi: 10.1016/j.jconrel.2023.08.014.
  5. Douka S, Papamoschou V, Raimo M, Mastrobattista E, Caiazzo M. Harnessing the Power of NK Cell Receptor Engineering as a New Prospect in Cancer Immunotherapy. Pharmaceutics 2024;16(9):1143. doi: 10.3390/pharmaceutics16091143.