Macrophage-mediated delivery of ganciclovir nanocomplexes inhibits the pathogenicity of Kaposi’s sarcoma-associated herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV), a member of the γ-herpesvirus family, is associated with the development of various malignancies. Ganciclovir (GCV) is a competitive inhibitor of DNA and can inhibit the synthesis of KSHV viral DNA polymerase. However, the water solubility of GCV makes it difficult to cross the cell membrane. Although nanocarriers are effective in delivering drugs into cells, they still face challenges in penetrating the dense tissue protected by the mucosal barrier. To address this, we developed macrophage-camouflaged nanoparticles as a drug delivery system, leveraging the innate tropism of macrophages to enhance tissue infiltration and therapeutic outcomes. This approach not only improves drug bioavailability but also minimizes off-target toxicity. In this study, we established an in vitro macrophage inflammation model to mimic the in vivo inflammatory microenvironment and employed ZIF-8 nanoparticles to encapsulate GCV, with hyaluronic acid (HA) as a targeting ligand. The in vivo and in vitro safety evaluations confirmed its excellent biocompatibility. The co-culturing experiment of induced macrophages loaded with nanodrugs with KSHV-positive cells showed that it can restrain proliferation and migration ability of KSHV-positive cells, and also reduce the expression of KSHV pathogenic genes. Collectively, our findings proposed a novel strategy utilizing macrophage-mediated delivery of HA/GCV@ZIF-8 nanomaterials to combat KSHV infection.