A first critical step was understanding how infected immune cells differ from healthy ones. To achieve this, the team developed a powerful screening strategy capable of identifying short molecular fragments that selectively recognize macrophages infected with tuberculosis bacteria. Through repeated testing in laboratory infection models, we assembled the first dedicated library of targeting molecules that bind specifically to infected cells. These efforts were supported by carefully controlled macrophage models that allowed detailed analysis of cell-surface features such as receptor abundance, sugar patterns, and electrical charge. Together, these tools form a reusable platform for discovering targeting strategies not only for tuberculosis, but also for many other intracellular pathogens.
Building on this molecular insight, PANDORA designed a new generation of nanoparticles capable of distinguishing infected cells from healthy ones with exceptional precision. These polymer-based particles were engineered so that the number and spacing of targeting molecules on their surface could be precisely controlled. Experiments revealed a striking switch-like behaviour: the nanoparticles ignored healthy cells entirely, but bound strongly once they encountered a cell displaying a sufficiently high density of infection-related markers. This effect arises not from a single strong interaction, but from the collective action of many weak ones working together. The discovery overturned a long-standing assumption in nanomedicine, that stronger binding automatically leads to better targeting, and showed instead that careful nanoscale organization can deliver superior selectivity. This principle, known as super-selectivity, has since become a reference point for targeted drug-delivery research.
PANDORA also made contributions beyond tuberculosis. During the COVID-19 pandemic, the team applied its expertise in nanoparticle stability to analyse the behaviour of an mRNA vaccine after preparation for clinical use. The results helped support vaccination logistics at a critical moment and were shared with the global scientific and medical community.
Beyond the laboratory, the project placed strong emphasis on communication and public engagement. Findings were disseminated through scientific publications, invited lectures, and innovative outreach activities, including a conference on the future of antibiotics and a public concert dedicated to antimicrobial resistance. By reshaping how scientists think about targeting, delivery, and resistance, PANDORA has laid the foundations for future therapies with real-world impact and contributed to the global effort to address one of the most pressing health challenges of our time.
