PolyElectrolyte Nanoparticles (PENs) obtained by layer-by-layer self-assembly of polycations/polyanions suffer from a lack of colloidal stability in physiological conditions. We report a simple innovative approach for increasing their stability by multiple ionic cross-linkers. Herein, a chitosan-based core was stabilized by polyanions such as tripolyphosphate and dextran sulfate at acidic and alkaline pHs to improve the quality of electrostatic interactions in the core and manage self-assembly of polyethyleneimine shell onto the core. Thereafter, the targeted polyelectrolyte nanoparticles (tPENs) by mannose were spray dried through a multiple-excipient including chitosan, leucine and mannitol to engineer novel Trojan particles for respiratory diseases. It was demonstrated that the non-toxic tPENs with high cellular uptake were successfully incorporated into microspheres with adequate emitted dose and fine particle fraction. Moreover, these novel aerosol powders can provide an effective approach for targeted therapy. Keywords: Targeted polyelectrolyte nanoparticles, Multiple ionic cross-linkers, Multiple-excipient, Trojan particles, Pulmonary delivery