Development of Chitosan Particles Loaded with siRNA for Cystatin C to Control Intracellular Drug-Resistant Mycobacterium tuberculosis

The golden age of antibiotics for tuberculosis (TB) is marked by its success in the 1950s of the last century. However, TB is not under control, and the rise in antibiotic resistance worldwide is a major threat to global health care. Understanding the complex interactions between TB bacilli and their host can inform the rational design of better TB therapeutics, including vaccines, new antibiotics, and host-directed therapies. We recently demonstrated that the modulation of cystatin C in human macrophages via RNA silencing improved the anti-mycobacterial immune responses to Mycobacterium tuberculosis infection. Available in vitro transfection methods are not suitable for the clinical translation of host-cell RNA silencing. To overcome this limitation, we developed different RNA delivery systems (DSs) that target human macrophages. Human peripheral blood-derived macrophages and THP1 cells are difficult to transfect using available methods. In this work, a new potential nanomedicine based on chitosan (CS-DS) was efficiently developed to carry a siRNA-targeting cystatin C to the infected macrophage models. Consequently, an effective impact on the intracellular survival/replication of TB bacilli, including drug-resistant clinical strains, was observed. Altogether, these results suggest the potential use of CS-DS in adjunctive therapy for TB in combination or not with antibiotics.

Automated summary

The golden age of antibiotics for tuberculosis in the 1950s has been overshadowed by the ongoing challenges in controlling the disease and the increasing global antibiotic resistance. Understanding the interactions between TB bacteria and their host can lead to the development of better therapeutics, such as vaccines and host-directed therapies. In this study, a potential nanomedicine based on chitosan (CS-DS) was developed to deliver siRNA targeting cystatin C to infected macrophages, resulting in improved immune responses and decreased intracellular survival of TB bacilli, including drug-resistant strains. These findings suggest the potential adjunctive use of CS-DS in TB therapy, either alone or in combination with antibiotics.