Patients with cystic fibrosis are highly susceptible to bacterial infections, which can often lead to irreversible damage. In this context, inhalable liposomal systems have shown great promise as drug delivery mechanisms, significantly enhancing drug permeation and accumulation in the lungs. However, the development of inhalable liposomes for various therapeutic applications is still in its early stages, providing ample opportunities for extensive research by the scientific community. Within this scenario, antimicrobial photodynamic therapy may emerge as a relevant technique, promoting greater selectivity due to its light trigger. We have developed lipid–polymer hybrid liposomes (DPPC/F127) and compare the inclusion of two types of xanthenes, one more hydrophilic (Rose Bengal - RB) and one more hydrophobic (Rose Bengal butyl ester - RBBUT). The systems were characterized in terms of morphology, thermal and kinetic stability, incorporation and release efficiency, photophysical properties, and possible location of the PS in the liposome. The studies showed that incorporation into DPPC/F127 prevented self-aggregation and significantly improved the photophysical properties of RB and RBBUT. The bacterium Pseudomonas aeruginosa proved to be more resistant to the photodynamic effect, requiring long illumination times. For Staphylococcus aureus, we observed a dependence between pre-incubation time and illumination time. Our results showed that the more external photosensitizer (PS) was more effective in experiments performed without incubation. However, with pre-incubation, the efficacy of both systems became comparable. Notably, only 10 min of illumination (warm white light; fluence: 139.7 J cm⁻2) resulted in complete bacterial inactivation.