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(N-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-co-glycolic acid). This was used to encapsulate siRNA targeting the green fluorescent protein (siGFP), within a lipid shell made from 1,2-dipalmitoyl-sn-glycero-3-phosphocholine and 1,2-distearoyl-sn-glycero-phosphoethanolamine-N-(polyethylene glycol)2000. 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.