Elita Montanari

Last Name

Montanari

First Name

Elita

ORCID

0000-0002-0551-5113

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Publications 1 - 5 of 5

Loading of Extracellular Vesicles with Nucleic Acids via Hybridization with Non-Lamellar Liquid Crystalline Lipid Nanoparticles
Bader, Johannes; Rüedi, Pascal; Mantella, Valeria; et al. (2025)
Advanced Science
The translation of cell-derived extracellular vesicles (EVs) into biogenic gene delivery systems is limited by relatively inefficient loading strategies. In this work, the loading of various nucleic acids into small EVs via their spontaneous hybridization with preloaded non-lamellar liquid crystalline lipid nanoparticles (LCNPs), forming hybrid EVs (HEVs) is described. It is demonstrated that LCNPs undergo pH-dependent structural transitions from inverse hexagonal (HII) phases at pH 5 to more disordered non-lamellar phases, possibly inverse micellar (L2) or sponge (L3) phases, at pH 7.4, which are particularly suitable for inducing a controlled hybridization process with EVs. State-of-the-art single-particle analysis techniques reveal that LCNPs interact with various EV subpopulations at physiological conditions and that ≈40% of HEVs are loaded with the genetic cargo. Importantly, this study demonstrates that EV membrane proteins remain accessible on HEV surfaces, with their intrinsic enzymatic activity unaffected after the hybridization process. Finally, HEVs show in vitro improved transfection efficiencies compared to unhybridized LCNPs. In summary, this versatile platform holds potential for loading various nucleic acid molecules into native EVs and may help developing EV-based therapeutics.
Inhibition of urease-mediated ammonia production by 2-octynohydroxamic acid in hepatic encephalopathy
Evstafeva, Diana; Ilievski, Filip; Bao, Yinyin; et al. (2024)
Nature Communications
Hepatic encephalopathy is a neuropsychiatric complication of liver disease which is partly associated with elevated ammonemia. Urea hydrolysis by urease-producing bacteria in the colon is often mentioned as one of the main routes of ammonia production in the body, yet research on treatments targeting bacterial ureases in hepatic encephalopathy is limited. Herein we report a hydroxamate-based urease inhibitor, 2-octynohydroxamic acid, exhibiting improved in vitro potency compared to hydroxamic acids that were previously investigated for hepatic encephalopathy. 2-octynohydroxamic acid shows low cytotoxic and mutagenic potential within a micromolar concentration range as well as reduces ammonemia in rodent models of liver disease. Furthermore, 2-octynohydroxamic acid treatment decreases cerebellar glutamine, a product of ammonia metabolism, in male bile duct ligated rats. A prototype colonic formulation enables reduced systemic exposure to 2-octynohydroxamic acid in male dogs. Overall, this work suggests that urease inhibitors delivered to the colon by means of colonic formulations represent a prospective approach for the treatment of hepatic encephalopathy.
Aberrant crosstalk between insulin signaling and mTOR in young Down syndrome individuals revealed by neuronal-derived extracellular vesicles
Perluigi, Marzia; Picca, Anna; Montanari, Elita; et al. (2022)
Alzheimer's & Dementia: The Journal of the Alzheimer's Association
Introduction: Intellectual disability, accelerated aging, and early-onset Alzheimer-like neurodegeneration are key brain pathological features of Down syndrome (DS). Although growing research aims at the identification of molecular pathways underlying the aging trajectory of DS population, data on infants and adolescents with DS are missing. Methods: Neuronal-derived extracellular vesicles (nEVs) were isolated form healthy donors (HDs, n = 17) and DS children (n = 18) from 2 to 17 years of age and nEV content was interrogated for markers of insulin/mTOR pathways. Results: nEVs isolated from DS children were characterized by a significant increase in pIRS1Ser636, a marker of insulin resistance, and the hyperactivation of the Akt/mTOR/p70S6K axis downstream from IRS1, likely driven by the higher inhibition of Phosphatase and tensin homolog (PTEN). High levels of pGSK3βSer9 were also found. Conclusions: The alteration of the insulin-signaling/mTOR pathways represents an early event in DS brain and likely contributes to the cerebral dysfunction and intellectual disability observed in this unique population.
Engineering Lipid Spherulites for the Sustained Release of Highly Dosed Small Hydrophilic Compounds
Montanari, Elita; Krupke, Hanna; Leroux, Jean-Christophe (2023)
Advanced Healthcare Materials
Currently, there is a lack of parenteral sustained release formulations for the delivery of highly dosed small hydrophilic drugs. Therefore, parenteral lipid spherulites are engineered capable of entrapping large amounts of such compounds and spontaneously releasing them in a sustained fashion. A library of spherulites is prepared with a simple green process, using phosphatidylcholine (PC) and/or phosphatidylethanolamine (PE), nonionic surfactants and water. The vesicle formulations exhibiting appropriate size distribution and morphology are selected and loaded with 4,6-di-O-(methoxy-diethyleneglycol)-myo-inositol-1,2,3,5-tetrakis(phosphate), ((OEG2)2-IP4), an inositol phosphate derivative currently under clinical evaluation for the treatment of aortic valve stenosis. The loading efficiency of spherulites is up to 12.5-fold higher than that of liposomes produced with the same materials. While the PC-containing vesicles showed high stability, the PE spherulites gradually lost their multilayer organization upon dilution, triggering the active pharmaceutical ingredient (API) release over time. In vitro experiments and pharmacokinetic studies in rats demonstrated the ability of PE spherulites to increase the systemic exposure of (OEG2)2-IP4 up to 3.1-fold after subcutaneous injection, and to completely release their payload within 3–4 d. In conclusion, PE spherulites represent a promising lipid platform for the extravascular parenteral administration of highly dosed small hydrophilic drugs.
Strategies to load therapeutics into polysaccharide-based nanogels with a focus on microfluidics: A review
Zoratto, Nicole; Montanari, Elita; Viola, Marco; et al. (2021)
Carbohydrate Polymers
Nowadays nanoparticles are increasingly investigated for the targeted and controlled delivery of therapeutics, as suggested by the high number of research articles (2400 in 2000 vs 8500 in 2020). Among them, almost 2% investigated nanogels in 2020. Nanogels or nanohydrogels (NGs) are nanoparticles formed by a swollen three-dimensional network of synthetic polymers or natural macromolecules such as polysaccharides. NGs represent a highly versatile nanocarrier, able to deliver a number of therapeutics. Currently, NGs are undergoing clinical trials for the delivery of anti-cancer vaccines. Herein, the strategies to load low molecular weight drugs, (poly)peptides and genetic material into polysaccharide NGs as well as to formulate NGs-based vaccines are summarized, with a focus on the microfluidics approach.

Publications 1 - 5 of 5

Elita Montanari

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