Diving into RNAi Therapy: An Inhalable Formulation Based on Lipid-Polymer Hybrid Systems for Pulmonary Delivery of siRNA.

Biomacromolecules

Lab of Biocompatible Polymers, Department of Biological, Chemical and Pharmaceutical Sciences and Technologies (STEBICEF), University of Palermo, Via Archirafi 32, Palermo 90123, Italy.

Published: December 2024

Here, a pulmonary formulation based on lipid-polymer hybrid nanoparticles carrying small interfering RNA (siRNA) was developed to realize a RNA interference-based therapy to treat respiratory diseases. Toward this aim, a new copolymer was synthesized, by functionalization of the α,β-poly(-2-hydroxyethyl)-d,l-aspartamide with 35 mol % of 1,2-bis(3-aminopropylamino)ethane, 0.4 mol % of fluorescent dye, and 4.5 mol % of poly(lactic--glycolic acid). This was used to encapsulate siRNA targeting the green fluorescent protein (siGFP), within a lipid shell made from 1,2-dipalmitoyl--glycero-3-phosphocholine and 1,2-distearoyl--glycero-phosphoethanolamine-N-(polyethylene glycol). siGFP-loaded lipid-polymer hybrid nanoparticles (LPHFNPs@siGFP) exhibited colloidal size (∼164 nm), positive ζ potential, high siRNA encapsulation efficiency (∼99%), and a core-shell morphology. They showed high cellular uptake and a gene silencing efficiency of ∼50% in human lung cancer cells expressing GFP. To address aerodynamic challenges, LPHFNPs@siGFP were spray-dried with trehalose, yielding spherical particles (∼3 μm) with 80% siRNA encapsulation efficiency, excellent aerosolization properties, and a gene silencing efficiency comparable to the fresh LPHFNPs@siGFP sample.

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Source
http://dx.doi.org/10.1021/acs.biomac.4c00387DOI Listing

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