Targeting matrix metalloproteinases activating and Indoleamine 2,3-dioxygenase suppression for triple-negative breast Cancer multimodal therapy

The dense extracellular matrix (ECM) and immunosuppressive tumor microenvironment represent two major challenges in the treatment of triple-negative breast cancer (TNBC). To address these obstacles, this study has developed a polymer micelle (NTP) for ECM remodeling and mitigation the immune microenvironment, based on activating endogenous matrix metalloproteinases (MMP) and suppression indoleamine 2,3-dioxygenase (IDO). Through self-assembly technology, this micelle effectively incorporates chemotherapy drugs (camptothecin (CPT) and cinnamaldehyde (CA)), reactive oxygen species (ROS) stimulants, nitric oxide (NO) donor and IDO inhibitor (NLG919), where CPT and CA have been reported to help generating ROS mainly in the mitochondrion. The guanidine group of poly-L-arginine (PArg), as an NO donor, can react with ROS to generate NO. The micelles aim to achieve significant therapeutic outcomes through robust drug penetration and anti-tumor immunity in multimodal therapy. They exhibit remarkable tumor tissue penetration ability, facilitating precise targeting of mitochondria and ROS production stimulation. Building upon this therapeutic foundation, the micellar system achieves in situ NO release, which effectively degrades the primary ECM through the activation of MMPs, while simultaneously promoting tumor cell apoptosis. Furthermore, the encapsulated NLG919 can be released and effectively mitigating the immunosuppressive milieu and triggering anti-tumor immune responses. Experimental results demonstrate that the micelles exhibit significant anti-tumor effects both in vitro and in vivo , accompanied by favorable biocompatibility. This study provides new insights into the application of subcellular targeting drug delivery systems in TNBC treatment, potentially heralding a new breakthrough in TNBC therapy.