Aerosolized Quercetin-Loaded Chia Seed Polysaccharide Nanoparticles: Design of Experiments and...

Background/Objectives: The recent advances in pulmonary delivery have shifted the paradigm to the development of inhalable drug-loaded polysaccharide particles that can be positioned at the respiratory interface while reducing the systemic exposure. Quercetin has broad anticancer activity but remains difficult to translate because of its poor aqueous solubility, limited bioavailability and rapid metabolic loss. Here, we report quercetin-loaded chitosan/Salvia hispanica polysaccharide nanoparticles as a natural polyelectrolyte nanocarrier for pulmonary delivery in lung cancer. Methods: Central composite design (CCD) and artificial neural network (ANN) models were used for mapping the factors to responses. Results: The models displayed a higher predictive accuracy and optimization reliability for identifying the optimized formulation. The optimized nanoparticles showed a quasi-spherical morphology (mean hydrodynamic diameter = 331 ± 14.34 nm) with cationic ζ-potential of +36.3 ± 2.56 mV and polydispersity index of 0.15. The optimized formulation showed acceptable powder-flow characteristics, an encapsulation efficiency of 73.8 ± 0.73%, drug loading of 14.20 ± 0.22%, and biphasic release with sustained quercetin release over 48 h. In A549 and H460 cell lines, nanoencapsulation increased the antiproliferative effect of quercetin relative to the free compound, yielding lower IC₅₀ values after 48 h of exposure. The nanoparticles showed greater suppression of wound closure, increased reactive oxygen species fluorescence and clear cellular uptake. Blank nanoparticles produced only limited effects. Conclusions: These results indicate that CCD/ANN-guided chitosan/Salvia hispanica polysaccharide nanoparticles provide a promising nanodelivery tool for quercetin delivery and enhanced in vitro activity in lung cancer cells, while the observed aerosol performance advocates further investigation of their pulmonary delivery potential.