Giordano, Sabrina (2025) ADVANCED BIOMATERIALS FOR PEPTIDE NUCLEIC ACID THERAPEUTICS: DESIGN AND DELIVERY VIA HYDROGELS AND NANOPARTICLE SYSTEMS. [Tesi di dottorato]

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Abstract

This doctoral research explores innovative delivery systems for oligonucleotide analogues, such as peptide nucleic acids (PNAs), which are key tools in biotechnology and medicine due to their programmability and ability to modulate biological reactions. Chemical modifications of oligonucleotides have enhanced stability and binding affinity, facilitating therapeutic strategies including antigene and antisense approaches that inhibit gene expression via transcriptional and post transcriptional mechanisms. Additionally, in vitro selection yields aptamers capable of antibody-like functions, emphasizing the versatility of modified nucleic acids as both research tools and therapeutic agents. Focusing on PNA-based delivery, the project addresses challenges posed by poor solubility and limited cellular uptake. The approach involves developing peptide based hydrogels via rational design and synthesis, which serve as biocompatible matrices with adjustable mechanical and chemical properties, high water content, and capacity for controlled release. These hydrogels can provide structural support and deliver nucleic acid therapeutics, including antisense PNAs, to specific cellular targets while overcoming stability and half-life limitations of free molecules. Complementarily, the research develops magnetite (Fe3O4) based magnetic nanoparticles (MNPs) functionalized with amphiphilic polymers for targeted PNA delivery. These superparamagnetic, field responsive nanoparticles harness biocompatibility for precise temporal and spatial therapeutic intervention. The synthesis, functionalization, and physicochemical characterization of these hybrid nanosystems are optimized to ensure stability and activity. In vitro experiments utilizing relevant cell cultures demonstrate effective gene expression interference, cellular uptake, and localized delivery, validating their therapeutic potential. Overall, this research demonstrates that combining oligonucleotide analogues with engineered biomaterials—specifically peptide hydrogels and magnetic nanoparticles—forms a versatile platform for controlled and targeted nucleic acid delivery. These systems function as adaptive matrices and guided vehicles, significantly advancing the development of multifunctional nucleic acid therapeutics with improved stability, specificity, and clinical translatability.

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