Résumé
Abstract The emergence and rapid propagation of infectious diseases, including the COVID‐19 pandemic, has evidenced the vulnerabilities in global health surveillance, the ease of transmission, and the imperative need for effective treatments. In this context, nanomedicines based on metal–organic frameworks (MOFs) have garnered great relevance as promising drug delivery platforms in a large range of complex diseases (e.g., cancer, and infections). However, most research has focused on sensing with scarce examples in antiviral therapies. Hence, here a pioneer combined 3‐in‐1 effect anti‐COVID pulmonary multitherapy based on the mesoporous iron(III) carboxylate MIL‐100(Fe) nanoparticles is proposed, with the proven intrinsic MOF effect, associated with favipiravir drug into their porosity and heparin on their external surface. A significant antiviral effect against a real scenario of COVID‐19 infection is demonstrated (≈70% inhibition), ensuring a suitable cellular viability. Further, a convenient pulmonary formulation is prepared based on mannitol‐based microspheres, testing its safety and biodistribution in healthy mice. No significant side effects are observed, reaching successfully the deep lungs, emphasizing a reduced immunological response compared to their controls. Therefore, these promising results open new horizons for future (pre)clinical trials targeting challenging infectious/pulmonary pathologies, enhancing the feasibility of designing customized therapeutic MOF platforms.