Tumor Microenvironment Specifically Regulated Nano Chemoamplifier for Chemosensitization and Activation of Anti-Tumor Immune Response by Coordinating Intracellular Magnesium Overload

<b>Background and objectives:</b> Chemotherapy is an established treatment modality for breast cancer; however, it is impaired by issues such as highly refractory chemoresistance and significant side effects. Magnesium ions (Mg²⁺), inorganic metal ions with anti-tumor bioactivity, sensitize cancer cells to chemotherapy by depressing P-glycoprotein (P-gp) expression. Moreover, Mg²⁺ functions as an immunoadjuvant to potentiate anti-tumor immune responses, while excessive Mg²⁺ can induce marked tumor cell apoptosis. <b>Methods:</b> To enable Mg²⁺ to serve as a chemotherapeutic adjuvant for enhanced treatment efficacy, a Trojan horse-like chemoamplifier, denoted as MMSN@Dox, endowed with tumor microenvironment (TME) responsiveness and capable of achieving chemotherapy sensitization and anti-tumor immune activation, was constructed to enhance the efficacy of breast cancer treatment. Leveraging Mg²⁺-enabled TME-responsive degradability of the chemoamplifier, density functional theory (DFT) simulations were conducted to elucidate carrier structural dynamics. <b>Results:</b> Under stimulation of TME, the chemoamplifier decomposes, accompanied by a substantial release of chemotherapeutic agents and metal ions. Excessive Mg²⁺ induces significant tumor cell apoptosis by triggering mitochondrial dysfunction and generating reactive oxygen species (ROS), and reinforces chemotherapy sensitivity by depressing P-gp expression. Furthermore, MMSN@Dox weakens the stemness of tumor cells, further enhancing chemotherapy. The remarkable tumor-killing capability of chemoamplifier MMSN@Dox led to a remarkable immunogenic cell death (ICD) effect. Combined with the regulatory function of Mg²⁺ on T cells, it ultimately activates anti-tumor immune responses and achieves exceptional anti-tumor performance in both in vitro and in vivo models. <b>Conclusions:</b> This approach, leveraging Mg²⁺ to enhance chemotherapy efficacy, establishes a new paradigm for overcoming chemotherapy resistance and offers a novel strategic avenue for advancing nanomedicine in breast cancer treatment.