Tumor Microenvironment-Responsive Proteolytic Nanodrug against Breast Cancer

Regulating the tumor microenvironment (TME) is essential not only for improving drug delivery but also for enhancing the efficacy of chemotherapy and immunotherapy. Proteolysis-Targeting Chimera (PROTAC) technology with durable and tunable therapeutic advantages offers possibilities for enhancing treatment efficacy. However, the strong biological activity of PROTACs may lead to uncontrolled degradation of proteins at off-target sites, thereby limiting their therapeutic efficacy in vivo. In this study, we introduce proteolytic nanodrugs specifically engineered to target and degrade the Smad3 protein, a key factor in fibroblast activation, through encapsulating small-molecule PROTACs in targeted nanocarriers. By targeting Smad3 in tumor tissues, proteolytic nanodrug effectively inhibits tumor-associated fibroblast activation, enhancing the penetration of chemotherapeutic agents within the tumor. When doxorubicin was combined with proteolytic nanodrug, exhibited a robust inhibitory effect on tumor growth. This approach offers a strategy for utilizing PROTACs to modulate the tumor microenvironment and optimize cancer treatment outcomes.