Pulmonary delivery of small interfering RNAs (siRNAs) has shown promising results for the treatment of lung diseases with gene disorders. The aim of this work was to evaluate the effect of processing-induced thermal and shear stresses during the spray drying process on the solid-state properties, the chemical integrity and the bioactivity of spray-dried siRNA powder intended for inhalation. To this end, inhalable siRNA dry powders composed of EGFP-siRNA and mannitol were prepared by using a lab-scale spray drier. Scanning electron microscopy (SEM), laser diffraction, and X-ray powder diffraction (XRPD) were used to characterize the solid-state properties of the spray-dried siRNA-mannitol powders. High performance liquid chromatography (HPLC) and flow cytometry were exploited to assess the chemical stability and cellular transfection efficiency of siRNA formulations, respectively. The results showed that the spray-dried particles changed from spherical to irregular shape with an increase in the inlet temperature. The high inlet temperature and intensive atomization conditions resulted in more agglomerates in the spray-dried particles. XRPD analysis indicated that the presence of siRNA affected the polymorphic form of mannitol in the spray-dried powder. Compromised chemical stability and cell transfection efficiency of siRNA were observed with an increase in the thermal stress and shear stress during the spray drying process. The chemical stability of siRNA in liquid state was more prone to thermal stress when compared to the stability in the solid-state. In conclusion, stable siRNA based particles for inhalation purposes could be produced using the spray drying technology.