Biomimetic and responsive nanoparticles loading JQ1 for dual-targeting treatment of vascular restenosis via multiple actions

Abstract

• The biomimetic and responsive DDS had optimized JQ1 release behavior and rapid homing to injured site. • The DDS inherited natural specificity for VSMCs from platelets and obtained dual-targeting function. • Pro-inflammatory cytokines secreted from macrophages were suppressed by the DDS. • The DDS can substantially inhibit VSMCs proliferation and intima hyperplasia with little effect on VECs. Postoperative restenosis remains the key problem of coronary arterial disease and seriously threatens human health. Currently, no effective strategies can thoroughly prevent restenosis owing to its complicated progression. We hypothesize the multi-effect drug of endothelium-protective epigenetic inhibitor (JQ1) may act well in anti-restenosis via exerting multiple functions and acting on different cells. Furthermore, homing to endothelium injured site and pH-triggered drug release can enhance targeted therapeutic efficacy by JQ1 preferential accumulation at injured site and in vascular smooth muscle cells (VSMCs). To verify our hypothesis and develop targeted drug delivery system (DDS) with controlled release ability for anti-restenosis, a pH-responsive nanoparticle was prepared to encapsulate JQ1 and further camouflaged by platelet membrane (PM). The resulting biomimetic and responsive DDS showed optimized drug release behavior and rapid homing to injured site. Moreover, the internalization of DDS in VSMCs was much higher than other groups without PM, which indicated that it inherited natural specificity for VSMCs from PM and obtained dual-targeting function to enhance therapeutic efficacy. The DDS presented significant anti-inflammatory effect via inhibiting NF-κB signaling pathway and secretion of pro-inflammatory cytokines from macrophages. Besides, VSMCs proliferation was suppressed by the DDS with little effect on vascular endothelial cell proliferation and in vivo re-endothelialization at suitable JQ1 concentration. More importantly, the DDS substantially inhibited intima hyperplasia without obvious pathological variation on main organs using a mouse model of carotid artery injury. In summary, we created a versatile DDS for the promotion of JQ1 targeting delivery and responsive release at injured site to mitigate restenosis. The DDS demonstrated outstanding performance via a synergistic and comprehensive effect of multiple factors for anti-restenosis, providing a promising method for clinical applications.