Proteins and other biomolecules sequestered in and delivered from polymeric drug delivery systems (DDS) undergo several process and storage-related stresses throughout the life of the product that can result in significant degradation and loss of bioactivity and raise safety concerns. [1-4] These stresses can include elevated temperatures, exposure to liquid and solid hydrophobic interfaces, and vigorous mechanical agitation. [1,5,6] A number of approaches have been developed to ameliorate the impact of individual stresses in emulsion-based methods. These include the use of interface stabilizers, [7,8] protein crystalization, [9] and covalent protein modification. [10] Ideally a single approach would protect against all these stresses, yielding excellent encapsulation efficiency and storage stability, while giving burst-free sustained release for any protein and polymer system of interest. Far from meeting this ideal, many approaches for improving one aspect of performance are neutral or deleterious to others. For example, solid-in-oil-in-water (s-o-w) emulsions [3] expose the protein to less solvent-based stress than do waterin- oil-in-water (w-o-w) methods; however, s-o-w methods have thus far led to reduced encapsulation efficiency or significant burst release. S-o-w vehicles incorporate proteins as a solid phase through freeze-drying or related processes, allowing inclusion of buffer salts, sugars, and other stabilizing additives. However, bulk freeze-drying yields relatively large protein particles, leading to poor dispersion in the final drug delivery product and burst release. [2,9] Smaller particles are necessary to give better dispersion and sustained delivery without burst. [2 ,9] Approaches such as spray-drying, spray-freeze drying, or freezedrying with polyethylene glycol (PEG) have been used to generate smaller stabilizer-bearing protein particles, but these are associated with low protein recovery [11] and can still result in burst release. [12] More recently, small protein particles have been precipitated from organic solvents. [9] However, this technique does not give good protein stability during storage, [9] may yield protein-dependent results, and still needs to be validated for therapeutic proteins. [9,13]. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.