Optimization of Lipoplexes Functionalized with a Sialic Acid Mimetic (F9-PEG) to Target the C1858T <i>PTPN22</i> Variant for Preclinical Assessment of a Novel Immunotherapy in Endocrine Autoimmunity

Optimization of Lipoplexes Functionalized with a Sialic Acid Mimetic (F9-PEG) to Target the C1858T <i>PTPN22</i> Variant for Preclinical Assessment of a Novel Immunotherapy in Endocrine Autoimmunity

<b>Background:</b> The C1858T <i>PTPN22</i> variant is strongly associated with type 1 diabetes and autoimmune thyroid disease. Current treatment is substitutive hormonal administration, which does not target the disease pathogenetic mechanism. We previously implemented a nov...

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Main Authors: Simona Sennato, Giorgia Paldino, Cecilia Bombelli, Irene Mezzani, Stefania Petrini, Domenico Vittorio Delfino, Francesco Fiorentino, Carlotta Marianecci, Alessia Ciogli, Dante Rotili, Francesca Ceccacci, Alessandra Fierabracci
Format: Article
Language:English
Published: MDPI AG 2025-05-01
Series:Pharmaceutics
Subjects:
type 1 diabetes
endocrine autoimmunity
immunotherapy
variant <i>PTPN22</i>
lipoplexes optimization
Online Access:https://www.mdpi.com/1999-4923/17/6/710
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Summary:<b>Background:</b> The C1858T <i>PTPN22</i> variant is strongly associated with type 1 diabetes and autoimmune thyroid disease. Current treatment is substitutive hormonal administration, which does not target the disease pathogenetic mechanism. We previously implemented a novel immunotherapy, employing siRNA directed against the C1858T variant of <i>PTPN22</i> delivered via functionalized lipoplexes, in order to halt autoimmune disease progression. <b>Objectives</b>: The objective of this study was to optimize lipoplex formulations functionalized with F9-PEG (a Siglec-10’s ligand) to facilitate targeted delivery by investigating their physical and chemical properties to warrant the best performance in in vivo studies. <b>Methods</b>: The effectiveness of siRNA liposome binding was evaluated by varying the relative lipid/siRNA charge ratio and analyzing the stability of the different formulations with respect to the methods of F9-PEG addition and ATTO740 fluorescent labeling by electrophoresis, dynamic and dielectrophoretic light scattering (DLS and DELS), and high-performance liquid chromatography (HPLC). <b>Results</b>: The optimal charge ratio of +2/−1 (lipid/siRNA) ensured a greater stability of lipoplexes and complete complexation of siRNA. Stability was improved by selecting a protocol of preparation that envisages functionalization with F9-PEG and the addition of ATTO740 lipid in the lipid film preparation step. HPLC confirmed the integrity of siRNA after preparation. <b>Conclusions</b>: The results of this study lead to formulations of F9-PEG lipoplexes with optimal properties that could be used for biodistribution and safety/efficacy studies in mice. Lipoplexes functionalized with F9-PEG could therefore represent a promising personalized nanotherapeutic platform for targeted siRNA delivery in endocrine C1858T patients.
ISSN:1999-4923

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