基于小分子药物、激素、环状激酶抑制剂和单克隆抗体的化疗已广泛应用于临床乳腺癌治疗，但其疗效有限，由于特异性差和肿瘤微环境（TME）引起的扩散障碍。虽然针对TME中的生物化学信号或物理信号开发了单一治疗方案，但两者都不能应对复杂的TME，而机械化学联合治疗仍有待探索。在此，我们开发了一种基于ECM调节剂和TME响应药物的联合治疗策略，首次尝试机械化学协同治疗乳腺癌。具体来说，基于乳腺癌中过表达的NAD（P）H醌氧还蛋白1（NQO1），我们设计了一种TME响应药物（NQO1-SN38），并与贡献于肿瘤硬度的Lysyl氧化酶（Lox）的抑制剂（即β-氨基丙腈，BAPN）结合，进行机械化学治疗。我们证明了NQO1能够触发NQO1-SN38的降解并释放SN38，在体外显示出近两倍于SN38治疗的肿瘤抑制效率。BAPN抑制Lox显著降低了肿瘤异种球体中胶原沉积并增强了药物的渗透。我们进一步证明，机械化学治疗在体内显示出卓越的治疗效果，为乳腺癌治疗提供了一种有前途的方法。本文受版权保护。所有权利均受保护。

Chemotherapy based on small molecule drugs, hormone, cycline kinase inhibitor and monoclonal antibody has been widely used for breast cancer treatment in the clinic but with limited efficacy, due to the poor specificity and tumor microenvironment (TME) caused diffusion barrier. Although mono-therapy targeting biochemical cues or physical cues in the TME have been developed, neither of them can cope with the complex TME, while mechanochemical combination therapy remains largely to be explored. Herein, we developed a combination therapy strategy based on ECM modulator and TME-responsive drug for the first attempt of mechanochemically synergistic treatment of breast cancer. Specifically, based on overexpressed NAD(P)H quinone oxidoreductase 1 (NQO1) in breast cancer, we designed a TME-responsive drug (NQO1-SN38) and combined it with the inhibitor (i.e., β-Aminopropionitrile, BAPN) for Lysyl oxidases (Lox) that contributes to the tumor stiffness, for mechanochemical therapy. We demonstrated that NQO1 could trigger the degradation of NQO1-SN38 and release SN38, showing nearly twice tumor inhibition efficiency compared with SN38 treatment in vitro. Lox inhibition with BAPN significantly reduced collagen deposition and enhanced drug penetration in tumor heterospheroids in vitro. We further demonstrated that the mechanochemical therapy showed outstanding therapeutic efficacy in vivo, providing a promising approach for breast cancer therapy. This article is protected by copyright. All rights reserved.This article is protected by copyright. All rights reserved.