Background and objectives: 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. Methods: 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. Results: 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. Conclusions: 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.

Mesoporous silica nanoparticles (MSNs), an excellent carrier material, have been widely used in tumor therapy as a vector for numerous therapeutic substances to boost therapeutical efficiency and specificity, such as loading them with chemotherapy drugs to improve the efficacy of chemotherapy. Nevertheless, they still face hurdles, such as lack of specificity and poor efficacy of monotherapy. The construction of multifunctional MSNs with excellent therapeutic effects by introducing metal ions has attracted the attention of many researchers. Herein, we demonstrated a calcium doped, chemotherapy drug doxorubicin (Dox) loaded, specific degradation nanoplatform, prepared using the sol–gel method by introducing calcium ions into an MSN framework, which enabled the doped nanoplatform to enhance chemotherapy and activate anti-tumor immune response. As a proof of concept, the doping of Ca²⁺ endowed MSNs with excellent specific degradation and pH responsive drug release, and enabled the synergy of chemotherapy and calcicoptosis. Furthermore, this nanoplatform also effectively elicited immunogenic cell death (ICD) and promoted the maturation of dendritic cells (DCs), realizing the activation of the anti-tumor immune system. The Ca²⁺ doped MSNs (CMSNs), that can activate immune response with specific degradation capability, demonstrate a practical strategy for the effective synergy between chemotherapy and calcicoptosis, providing a new paradigm for promoting chemotherapy-related treatment.