Lung surfactant-hydrogel nanocomposites for pulmonary siRNA delivery: breaching barriers for nanomedicine-based inhalation therapy

Promovendus/a: Pieterjan Merckx

Promotor(en): Prof. dr. Koen Raemdonck, Prof. dr. Stefaan De Smedt

The upsurge in global prevalence of non-infectious inflammatory lung diseases highlights the demand for novel therapies to address the associated unmet medical needs. In that regard, exploiting the intracellular RNA interference (RNAi) pathway through small interfering RNA (siRNA) has opened prospects for a novel disease-modifying therapeutic approach, as it allows potent and highly specific silencing of virtually any gene. Yet, the clinical implementation of siRNA inhalation therapy has so far been held back by the lack of safe and efficient delivery vectors for administration. To this end, we developed pulmonary surfactant-coated nanogels for local pulmonary siRNA delivery. The proposed nanocomposite merges the benefits of a biodegradable, controlled release hydrogel core with a lipid-protein bilayer coating based on the composition of human pulmonary surfactant. The latter improves the formulation’s biocompatibility and stability, combined with the recent finding that it enhances the relative cellular siRNA delivery. We isolated the main components of pulmonary surfactant necessary to obtain this enhanced siRNA delivery effect, among which surfactant protein B (SP-B) that was identified as being the essential element. Hence, this allowed us to design a nanocomposite with a simplified, SP-B-based coating, for which we demonstrated efficient siRNA delivery in vitro an in vivo. In addition, we explored the potential of β2-agonists to be repurposed as adjuvants for siRNA delivery subsequent to nanocomposite treatment. As a final step, the formulation was shown to be suitable for preservation as a dry powder through lyophilization and administration via nebulization. Altogether, the proof-of-concept data in this work pave the way for pulmonary surfactant coated nanogels towards clinical translation as a novel delivery vector for siRNA inhalation therapy.