DCR2-targeted ultrasound nanobubbles loaded with verteporfin promote M2 macrophage polarization to overcome doxorubicin resistance in breast cancer

Doxorubicin (Dox) has been a mainstay in breast cancer treatment for over three decades, but its therapeutic efficacy is often compromised by drug-induced senescence, leading to therapeutic failure. Thus, this underscores the need for innovative therapeutic strategies in breast cancer therapy. To address this challenge, we have identified DCR2, a cell membrane marker of senescent cells, and developed DCR2-targeted ultrasound nanobubbles to counteract Dox-induced senescence in breast cancer. The results showed that DCR2-targeted nanobubbles exhibited a robust ultrasound signal around senescent breast cancer cells and can encapsulate verteporfin (Ver), a phagocytosis inhibitor, to suppress Dox-induced senescence and inhibit breast tumor growth. Notably, using two breast tumor models in MMTV-PyVT and C57BL/6 mice, we showed that DCR2-targeted ultrasound nanobubbles can modulate tumor immune microenvironment and reverse senescence-induced polarization of M2 tumor-associated macrophages. The tumor growth was markedly suppressed by the combined treatment of Dox and Ver-loaded DCR2-targeted nanobubbles. In summary, this study presents a promising approach to overcoming chemotherapy resistance using ultrasound nanobubbles, providing potential improvements in breast cancer treatment outcomes.