Brusco, Susy (2025) Tackling lung barriers to inhaled drugs through engineered nanoparticles. [Tesi di dottorato]

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Abstract

The treatment of severe respiratory diseases remains a significant clinical challenge, particularly when delivering sensitive biomacromolecules, such as proteins and nucleic acid (NA) therapeutics. Inhalation has emerged as an effective route of administration, offering the advantage of direct drug delivery to the lungs, which enhances local drug concentration while minimizing systemic exposure and toxicity. However, the pulmonary environment poses several biological barriers, including mucociliary clearance, enzymatic degradation, and tight epithelial junctions, which can significantly limit drug absorption and therapeutic efficacy. With this idea in mind, the present thesis focuses on the design and development of inhalable nanoparticles (iNPs) for the pulmonary delivery of protein and NA therapeutics, aiming to enhance drug cargo stability, targeting, and bioavailability within lung tissue. Depending on the specific therapeutic payload, three distinct nanoplatforms were developed by engineering the surface of the poly(lactic-co-glycolic) acid (PLGA) core with various lipid components, both synthetic and biologically derived, tailored to meet specific therapeutic requirements. In all cases, surface engineering was strategically employed to modulate the interaction of iNPs with lung lining fluids and to enhance the internalization in the target cell. In the context of mucosal vaccination, monophosphoryl lipid A (MPLA) and DSPE-PEG (1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N [carboxy(polyethylene glycol)-2000]) were selected. MPLA acted as a potent immune stimulating adjuvant, while DSPE-PEG provided steric stabilization and improved mucus penetration. This system was designed to co-deliver antigens and immune modulators, aiming to elicit a robust local immune response against pulmonary pathogens. To harness RNA therapeutics for inhalation, other lipid components, such as dipalmitoylphosphatidylcholine (DPPC) and ionizable lipids, were utilized to enhance nanoparticle interaction with pulmonary cells and to promote endosomal escape, a key step for efficient RNA delivery. Additionally, extracellular vesicles were explored as a natural and biocompatible alternative for nanoparticle surface functionalization, offering intrinsic targeting capabilities and improved biological interactions. A key focus of this work was the full optimization of the nanoplatforms in terms of critical quality attributes for pulmonary delivery. Subsequently, their interaction with relevant biological fluids, such as mucus, were investigated, followed by the evaluation of drug activity at the cellular level. Biophysical complementary techniques, such as SAXS (Small-angle X-ray scattering) and DSC (Differential Scanning Calorimetry), and computational tools, were crucial to fill in the picture of nanoparticle structure and to understand how composition and surface chemistry affect therapeutic performance in the pulmonary setting. Overall, this thesis confirms the potential of rationally engineered, lipid engineered PLGA hybrid nanoparticles as advanced drug delivery systems for the treatment of respiratory diseases. By tailoring surface modifications to specific therapeutic needs, ranging from mucosal immunization to gene delivery, this work offers insights to support the development of more effective, tailored, and patient-friendly inhalation therapies.

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