Mannose-Functionalized Polymeric Micelles Target CD206-Expressing Macrophages Within Human Tuberculosis Granulomas and Improve Isoniazid Delivery

Background: Latent tuberculosis infection (LTBI) remains a global health challenge, in part due to the ability of Mycobacterium tuberculosis (Mtb) to persist within granulomatous lesions where drug exposure may be limited. Because granulomas are heterogeneous structures composed of different macrophage populations, targeting disease-relevant intracellular niches may improve antimicrobial treatment. Here, we developed mannose-functionalized polymeric micelles loaded with isoniazid (INH) to target mannose receptor (CD206)-expressing macrophages within a human tuberculosis granuloma model. Methods: Mannose-functionalized Soluplus® micelles loaded with INH (ManPM-INH) and non-functionalized micelles (PM-INH) were characterized for particle size, polydispersity, and colloidal stability. Antimycobacterial activity against MtbH37Rv was evaluated by CFU assays. A human peripheral blood mononuclear cell (PBMC) three-dimensional in vitro granuloma model was used to assess micelle accumulation and antimycobacterial activity. Cellular uptake was evaluated in M0, M1, and M2 macrophages using rhodamine-labeled micelles. CD206-associated and clathrin-mediated uptake were investigated using D-mannose and chlorpromazine, respectively. Results: ManPM-INH exhibited suitable physicochemical properties and maintained colloidal stability after mannose functionalization. In the granuloma model, ManPM showed significantly greater intracellular accumulation than PM. M2-like macrophages predominated within granulomas, and ManPM displayed preferential uptake by M2 macrophages. Furthermore, D-mannose competitively reduced ManPM uptake in macrophages with significantly greater inhibition in M2 cells. Chlorpromazine reduced ManPM internalization, supporting involvement of a clathrin-dependent pathway. ManPM-INH achieved the greatest reduction in intracellular MtbH37Rv burden compared with INH and PM-INH, particularly at low drug concentrations. Conclusions: Mannose-functionalized micelles enhance intracellular INH delivery by targeting CD206-expressing macrophages within tuberculosis granuloma, supporting macrophage-targeted nanotherapeutic strategies against persistent intracellular Mtb.