It is now well-established that respiratory viruses can be transmitted by the airborne route, yet the parameters modulating the infectivity of viruses in aerosol particles are poorly understood. Through a combined experimental and computational approach, we have previously demonstrated the importance of air composition and resulting aerosol pH on virus persistence in aerosol particles. We identified that aerosol acidification after exhalation is a major driver of virus inactivation. However, the virus persistence also depends on the composition and properties of the respiratory matrix. Some matrix components, as well as phase transitions during aerosol drying, may promote or diminish virus inactivation. To better characterize matrix effects on virus persistence, we investigated the inactivation of influenza A virus (A/WSN/33) in 1-μl droplets of inorganic buffer, synthetic lung fluid and mucus harvested from primary epithelial nasal cells at 8 various relative humidities ranging from 15% to 95%. We showed that when RH was below 80%, the virus inactivation was reduced in those latter two matrices, both containing organics, compared to the saline solution. Albumin, a protein commonly present in respiratory tract lining fluid, was identified as an efficient protective agent. In addition, the protective effect of organics during crystallization at low and medium RH was investigated. First, the crystallization of a pure NaCl solution at RH ≤ 60% proved to reduce virus persistence, underlining the importance of phase transition in aerosol particles. However, the addition of organics such as sucrose and albumin in the fluid matrix was found to shield virus from inactivation, despite crystallization. Interestingly, the virus itself was identified as a condensation nucleus, leading to crystallization of very viscous NaCl-sucrose droplets containing virus compared to virus-free droplets in which efflorescence is usually inhibited. All of the above emphasizes the importance of accurately capturing both the composition of the respiratory matrix and the presence of the virus when experimentally or computationally investigating airborne virus transmission.