Sonosensitive Nanomedicine For Microenvironment Multi-Mechanistic Remodeling Of Oral Cancer

A sonosensitive nanomedicine was constructed for treatment of oral squamous cell carcinoma (OSCC), which is an aggressive tumor that has a limited response rate to immunotherapy, and invades bone easily when adjacent. Nanoprecipitation was used to establish a nanoplatform with sonosensitizer verteporfin (Vp) and EZH2 inhibitor tazemetostat (Taz). Then, extruding method was used to wrap macrophage membrane (MM) on this nanoplatform to prepare MMVT. Characterization was conducted by analyzing size, zeta potential, morphology, sonodynamic performance, RANKL scavenging effect and stability. In vitro sonodynamic ablation effects were detected using OSCC cell line SCC7. Then, sonodynamic therapy-induced immune activation, and epigenetic regulation effect of Taz on further enhancing immunotherapy response were assessed. Bone marrow-derived macrophages from C57BL/6 mice were used to evaluate osteoclast inhibition effect. Finally, in vivo synergistic antitumor effects were evaluated using OSCC orthotopic model with bone invasion on C57BL/6 mice through intravenous administration of MMVT. MMVT exhibited a core-shell spherical nanostructure with excellent sonodynamic performance, RANKL scavenging effect, and good serum stability. The results of both in vitro and in vivo showed that MMVT can be used for localized tumor ablation, generation of tumor antigens to activate antitumor immune response, and ultrasound responsive Taz release for amplifying the antitumor immunity and inhibiting osteoclast formation. Moreover, MM coating realized drug targeting delivery to OSCC, and RANKL scavenging for further inhibiting bone resorption. The nanomedicine can integrate multiple functions of sonodynamic ablation, antitumor immune activation and osteoclast inhibition, remodeling the microenvironment multi-mechanistically for OSCC treatment.