Gas-filled hollow nanoparticulate aggregates designed for use as an ultrasound contrast agent and as an ultrasound-mediated nanoparticulate drug delivery vehicle are manufactured by spray drying of nanoparticulate suspension at a fast convective drying rate. The gas outward diffusion from the hollow particles during insonication reduces the shell mechanical stability hence shortening the lifespan of the ultrasound contrast agent. The present work aims to develop a formulation method to produce micron-size hollow nanoparticulate aggregates with high shell mechanical stability by controlling the shell thickness-to-particle radius (S/R) ratio. The impacts of changing (1) the spray drying parameters, (2) nanoparticulate suspension concentration, and (3) surfactant inclusion (i.e. phospholipids) on the particle morphology and the S/R ratio are investigated. Biocompatible PMMA-MeOPEGMA nanoparticles of varying sizes (i.e. 50 ± 20, 110 ± 40, and 230 ± 80 nm) are used as the model nanoparticles. The results indicate that the S/R ratio increases with decreasing particle size and the shell mechanical stability is linearly dependent on the S/R ratio. The effects of the spray drying parameters and nanoparticle concentration are found to be minimal in the absence of the phospholipids. The S/R ratio can be significantly increased by using larger size nanoparticles with the phospholipids inclusion.