Targeted polydopamine/MSN delivery system to enhance the anti-breast tumor efficacy by inducing ferroptosis and synergistic chemotherapy and immunology effect

The combination of ferroptosis with chemotherapy and immunotherapy is a novel cellular mechanism with significant implications for antitumor therapeutic strategies. It can mitigate toxic damage to normal tissues and cells, while potentiating antitumor immune responses. In this study, we propose a multi-mechanism nanosystem that utilizes amino-modified mesoporous silica (MSNs-NH 2 ) as carriers. These nanoparticles are loaded with doxorubicin (DOX) and the immunomodulator all-trans retinoic acid (ATRA), followed by coating with polydopamine (PDA). A hybrid nanosystem featuring a core/shell structure was fabricated by chemically chelating ferrous lactate onto PDA coating. It was subsequently conjugated with RGD-targeting peptides (RFP/MN@D/A). In vitro experiment results revealed that RFP/MN@D/A possessed pH/H 2 O 2 dual-responsive drug release characteristics, and could be efficiently internalized by MCF-7 cells. Exogenous Fe 2+ activated the Fenton reaction in the acidic tumor microenvironment (TME), generating an abundance of reactive oxygen species (ROS) that attack membrane phospholipids. This attack led to cytotoxic free radical production and thereby induced ferroptosis. Additionally, following gradual rupture of the PDA coating, DOX and ATRA were released responsively. This release triggered immunogenic cell death (ICD) and apoptosis through multiple mechanisms, including HMGB1 release, cell cycle arrest, and mitochondrial dysfunction. In tumor-bearing mice, RFP/MN@D/A exhibited superior tumor growth inhibitory activity alongside good biosafety profiles. Collectively, the functionalized delivery system developed in this study has significant potential for modulating immune responses and inducing ferroptosis through targeted delivery coupled with multiple responsive release strategies. This approach synergizes effectively with chemotherapy to achieve enhanced therapeutic efficacy against breast tumors, with broad application prospects for solid cancer treatment. Download: Download high-res image (419KB) Download: Download full-size image