Macrophage‐Mediated Delivery of miR‐34a‐5p‐Nanoparticles for Pathogenic Inhibition of Kaposi's Sarcoma‐Associated Herpesvirus

Kaposi's sarcoma-associated herpesvirus (KSHV) has been demonstrated to trigger a variety of malignant neoplasms, however, there are currently no targeted pharmaceutical interventions available. MicroRNA(miRNA)-based antiviral and tumor therapies are frequently utilized, yet the challenges of cellular uptake and susceptibility to degradation underscore the necessity for a delivery system that can effectively combat KSHV. Nonetheless, despite the efficacy of nanocarriers in delivering drugs into cells, they continue to encounter challenges in penetrating the brain. In this study, a macrophage inflammation model was developed to enhance the delivery of miR-34a-5p loaded by folic acid-modified β-cyclodextrin grafted polyethyleneimine (β-CD-PEI-FA) nanocomposites, based on FA targeted to folate receptors on the surface of macrophages and tumor cells. Both in vivo and in vitro safety evaluations of the nanocarriers were performed, which confirmed the exceptional biocompatibility. Assays involving the coculture of induced nanodrug-loaded macrophages and KSHV-positive cells demonstrated the efficient delivery of miR-34a-5p into KSHV-positive cells through macrophages. This delivery led to the inhibition of the proliferation and cell cycle of cocultured KSHV-positive cells, as well as a significant reduction in the expression of KSHV pathogenic genes RTA and v-GPCR. Notably, fluorescence imaging of organs revealed the in vivo delivery of nanocomposites into brain tissues, including tumors. Furthermore, immunohistochemistry analysis revealed increased macrophages infiltration in both tumors and brain tissues in xenograft mice. In conclusion, our study presents a pioneering strategy employing macrophages as carriers for delivering β-CD-PEI-FA/miR-34a-5p nanocomplexes in anti-KSHV therapy.