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Addressing the Challenge of Respiratory Ribonucleic Acid Therapeutics with Inhalable Hybrid Lipid-Polymer Nanoparticles

Ungaro F.

Respiratory Drug Delivery 2025. Volume 1, 2025: 39-48.

Abstract:

As respiratory medicine advances, research focus is shifting toward nucleic acid therapeutics, like ribonucleic acids (RNAs), for treating life-threatening lung diseases. However, the challenges faced by inhaled RNAs highlight the critical need for safe and effective delivery systems to move these therapies from bench to bedside. Lipid and polymer nanoparticles offer the unprecedented opportunity to fill this gap but need to be engineered for inhalation. Inhaled nanoparticles (iNPs) must fulfil two critical requirements: (i) to gain appropriate deposition at lungs; (ii) to overcome in situ biological barriers preventing access to the target. The complex and heterogeneous nature of the lung milieu strongly impacts the targeting efficiency of the carrier, creating a gap between iNP development and clinical application. This challenge is amplified for RNA therapeutics, which are required to cross the cell membrane gaining access into the cytoplasm/nuclei, likely escaping endo-lysosomal degradation. A recently explored strategy to develop mucus- and cell-penetrating iNPs involves the use of hybrid lipid-polymer nanoparticles, featuring a core made of a biocompatible and biodegradable poly(lactic-co-glycolic acid) (PLGA) surrounded by a lipid shell (lipid@PLGA hNPs). Recent developments regarding lipid@PLGA hNPs loaded with short-interference RNAs (siRNAs) are outlined along with perspectives to optimize the hNP composition and production process and to translate this approach from the laboratory bench to industry.