Pochet, A.; Bourguignon, T.; Grande, A.; Alfredo Godinez-Leon, J.; Fine, J.; Brodin, P.; Machelart, A.; Gref, R.

In response to the escalating threat of infectious diseases and the widespread emergence of antimicrobial-resistant strains, novel therapeutic strategies are being actively developed. Nanoparticle-based delivery systems have emerged as promising tools to improve the targeted administration of antimicrobials directly to sites of infection. In the context of pulmonary infections, aerosolized nanocarriers can enhance local biodistribution while minimizing systemic exposure and associated side effects. In this study, we demonstrate that following pulmonary administration in Mycobacterium tuberculosis-infected mice, poly(lactic-co-glycolic acid) (PLGA) nanoparticles are broadly distributed throughout the lungs and preferentially interact with alveolar macrophages, the primary host cells of the pathogen. Remarkably, infected macrophages internalize significantly more nanoparticles than uninfected cells independently of the virulence and viability of the bacteria. Using transcriptomic analysis, we uncovered a list of 21 commonly modulated genes that may be responsible for this phenotype. Collectively, our findings reveal a striking feature of nanoparticles: their capacity to selectively accumulate in infected cells, offering a powerful mechanism to enhance antimicrobial delivery precisely where it is most needed.