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[Display omitted] • The internal microstructure of dried particles varies with excipients. • Viral activity decreased as the total (internal + external) solid-air interfacial area increased. • The viral vector analogue is predominantly located at or near the solid-air interfaces. • Surface area within spray dried particles is an indicator of activity. • Internal voids can mask the effects of operating conditions and excipient selection. To maintain the activity of sensitive biologics during encapsulation by spray drying, a better understanding of deactivation pathways in dried particles is necessary. The effect of solid-air interfaces within dried particles on viral deactivation was examined with three binary excipient blends, mannitol/dextran (MD), xylitol/dextran (XD), and lactose/trehalose (LT). Particles encapsulating human serotype 5 adenovirus viral vector (AdHu5) were produced via both spray drying and acoustic levitation. The particles' internal microstructure was directly visualized, and the location of a viral vector analogue was spatially mapped within the particles by volume imaging using focused ion beam sectioning and scanning electron microscopy. The majority of the viral vector analogue was found at, or near, the solid-air interfaces. Peclet number and crystallization kinetics governed the internal microstructure of the particles: XD particles with minimal internal voids retained the highest viral activity, followed by MD particles with a few large voids, and finally LT particles with numerous internal voids exhibited the lowest viral activity. Overall, AdHu5 activity decreased as the total solid-air interfacial area increased (as quantified by nitrogen sorption). Along with processing losses, this work highlights the importance of surface area within particles as an indicator of activity losses for dried biologics. [ABSTRACT FROM AUTHOR]