Ultrastable cerasomes nanoplatform co-delivering sonosensitizer and Nrf2 inhibitor for enhanced sonodynamic therapy of triple-negative breast cancer

This study develops a cerasome-based nanoplatform (ML385@PC-iRGD) stabilized by a siloxane surface network for enhanced systemic stability. It effectively targets and accumulates in tumors via iRGD. Under ultrasound, it generates reactive oxygen species (ROS), while the co-delivered ML385 inhibits the Nrf2 antioxidant pathway. This “ROS burst + defense blockade” strategy synergistically overcomes the intrinsic resistance of triple-negative breast cancer to oxidative therapies. • A sonodynamic therapy and Nrf2 inhibitor synergistic strategy is developed to enhance ROS-mediated anticancer efficacy. • This strategy overcomes therapy resistance by suppressing the antioxidant defense system in triple-negative breast cancer cells. • An engineered ultra-stable cerasome nanocarrier significantly minimizes drug leakage during systemic circulation. • The targeting specificity of the nanoplatform is substantially improved through surface modification with iRGD peptides. Triple-negative breast cancer (TNBC) is an aggressive malignancy characterized by poor prognosis, limited treatment options, and resistance to conventional therapies. Sonodynamic therapy (SDT) has emerged as a promising non-invasive approach that leverages ultrasound to activate sonosensitizers and generate cytotoxic reactive oxygen species (ROS). However, the therapeutic efficacy of SDT is frequently compromised by the overactivation of antioxidant pathways, notably the Keap1-Nrf2-ARE axis. In this study, we developed a multifunctional and ultrastable cerasome-based nanoplatform (ML385@PC-iRGD) that co-delivers a porphyrin-based sonosensitizer and the Nrf2 inhibitor ML385, with surface functionalization by the tumor-penetrating peptide iRGD. The cerasomes, stabilized by a siloxane surface network, exhibited excellent stability and prolonged circulation time. In vitro and in vivo studies demonstrated that ML385@PC-iRGD efficiently accumulated in tumors, enhanced cellular uptake via iRGD-mediated targeting, and triggered robust ROS production under ultrasound irradiation. Importantly, the co-delivery of ML385 suppressed Nrf2-driven antioxidant defenses, leading to amplified oxidative stress. This synergistic “ROS burst + defense blockade” strategy effectively overcome the intrinsic resistance of TNBC to oxidative therapies. Overall, our study highlights the potential of cerasome-based nanocarriers as a powerful and stable delivery system for combinatorial SDT and molecular inhibition, offering a promising therapeutic avenue for the treatment of refractory breast cancers.