Dry powder inhaler (DPI) delivery of therapeutic nanoparticles requires the nanoparticles to be transformed into inhalable micro-scale aggregate structures (i.e. nano-aggregates). The present work details the spray-freeze-drying (SFD) production of dry-powder aggregates of thermally-sensitive polymeric nanoparticles. Specifically, the aim is to optimize the aerosolization efficiency of the nano-aggregates, while keeping the morphology, production yield, flowability, and aqueous reconstitution in the desirable range. For this purpose, the effects of SFD process parameters (i.e. atomization rate, feed concentration, and feed rate) and freeze-drying adjuvant formulation on the nano-aggregate characteristics are examined. Low melting-point poly (caprolactone) (PCL) nanoparticles are used as the model nanoparticles. Mannitol and leucine are used as the hydrophilic and hydrophobic adjuvants, respectively. Large spherical porous nano-aggregates, where PCL nanoparticles are physically dispersed in the porous adjuvant matrix, have been produced. The presence of mannitol is crucial in ensuring that the nano-aggregates readily reconstitute into individual nanoparticles upon exposure to an aqueous environment, so that they can perform their intended therapeutic functions. The presence of leucine, on the other hand, is mandatory to obtain high aerosolization efficiency as its presence reduces the nano-aggregate tendency to agglomerate. At the optimal condition, nano-aggregates exhibiting ED (Emitted Dose) approximate to 95%, FPF (Fine Particle Fraction) approximate to 30%, and MMAD (Mass Median Aerodynamic Diameter) approximate to 5.3 mu m, which are comparable to the values obtained in commercial DPI, have been produced. The results signify the potential of SFD to be employed in the production of inhalable dosage form of thermally-sensitive therapeutic nanoparticles. (c) 2011 Elsevier B.V. All rights reserved.