The present study focuses on the development of multi-trigger responsive surface active lipid nanovesicles encapsulating paclitaxel with the hypothesis that pulmonary surfactant mimetic lipid vesicles sensitive to temperature and enzyme simultaneously will offer synergistic advantage towards improved therapeutic efficacy of paclitaxel via aerosol administration. The nanovesicles showed a unimodal size distribution of the particles (100-150 nm) and high encapsulation efficiency of paclitaxel (82%). Triggered release of paclitaxel was observed at ∼42 °C in the presence of secretory phospholipase A(2) enzyme with maximum release observed with both the triggers used simultaneously. Since these nanovesicles are intended for aerosol administration in the treatment of lung cancer, they were engineered to have high surface activity and airway patency, in order to mimic pulmonary surfactant functions. High deposition of nanovesicles in the lower impingement chamber of a twin impinger upon nebulization suggested them to be capable of reaching the terminal regions of the lungs. Nanovesicles showed facilitated and ATP dependent active uptake by A549 cells. The cytotoxic potential of the nanovesicles was significantly increased upon simultaneous use of both the triggers with an IC(50) of 49.3 nM. Overall, these studies suggest the therapeutic potential and advantages of multi trigger responsive lipid nanovesicles with encapsulated paclitaxel over that of the commercially available form of paclitaxel namely Taxol, and suggests the feasibility of aerosol administration in the treatment of lung cancer and pulmonary metastasis.