<p>Oral squamous cell carcinoma (OSCC) is an aggressive tumor that metastasizes frequently and invades the maxillary or mandibular bone easily when adjacent to the jaw bone. Caused by tumor-induced osteoclasts activation, bone invasion could release various cytokines from bone matrix that further promote cancer progression, leading to a bone-associated tumor vicious cycle and poorer prognosis. Herein, two clinical used small molecular drugs, verteporfin (Vp) and tazemetostat (Taz), are repurposed for off-label application and cleverly self-assembled into nanomedicine for dual eradicating cancer cells and inhibiting bone destruction. Specifically, Vp can be used for sonodynamic activation-mediated localized tumor ablation and generation of tumor antigens to activate antitumor immune response. EZH2 inhibitor Taz can amplify the antitumor immune response and inhibit bone invasion, when combining roles of Taz in epigenetically regulating tumor immunogenicity elevation and osteoclast inhibition. Moreover, macrophage membrane is utilized to encapsulate the nanomedicine to facilitate targeted drug delivery to OSCC and RANKL scavenging for osteoclast inhibition, aiding the microenvironment multi-mechanistic remodeling for synergistic therapy. Enhanced therapeutic outcomes have benefited from the nanodecoys in vivo via the animal model of OSCC with mandible invasion. Collectively, these results highlight the attractive functions of macrophage membrane-cloaked nanomedicine for effective and safe treatment against OSCC.</p> Graphical abstract <p></p>