Overproduction of reactive oxygen species (ROS), metal ion accumulation, and tricarboxylic acid cycle collapse are crucial factors in mitochondria‐mediated cell death. However, the highly adaptive nature and damage‐repair capabilities of malignant tumors strongly limit the efficacy of treatments based on a single treatment mode. To address this challenge, a self‐reinforced bimetallic Mito‐Jammer is developed by incorporating doxorubicin (DOX) and calcium peroxide (CaO ₂ ) into hyaluronic acid (HA) ‐modified metal‐organic frameworks (MOF). After cellular, Mito‐Jammer dissociates into CaO ₂ and Cu ²⁺ in the tumor microenvironment. The exposed CaO ₂ further yields hydrogen peroxide (H ₂ O ₂ ) and Ca ²⁺ in a weakly acidic environment to strengthen the Cu ²⁺ ‐based Fenton‐like reaction. Furthermore, the combination of chemodynamic therapy and Ca ²⁺ overload exacerbates ROS storms and mitochondrial damage, resulting in the downregulation of intracellular adenosine triphosphate (ATP) levels and blocking of Cu‐ATPase to sensitize cuproptosis. This multilevel interaction strategy also activates robust immunogenic cell death and suppresses tumor metastasis simultaneously. This study presents a multivariate model for revolutionizing mitochondria damage, relying on the continuous retention of bimetallic ions to boost cuproptosis/immunotherapy in cancer.

Rationale: Multidrug resistance (MDR) and metastasis of breast cancer remain major hurdles in clinical anticancer therapy. The unsatisfactory outcome is largely due to insufficient cytotoxicity of chemotherapeutic agents and limited immunogenic cell death (ICD). On the other hand, efflux proteins, especially P-glycoprotein (P-gp), can recognize and promote the efflux of drugs from tumor cells.

The emergence of aggregation‐induced emission luminogens (AIEgens) has attracted substantial scientific attention. However, their antitumor efficacy in photodynamic therapy (PDT) is significantly restricted by the poor water solubility and limited treatment depth. Therefore, a novel AIEgens‐involved therapeutic platform with good permeability and bioavailability is urgently required. Herein, supramolecular chemistry is combined with the AIEgen bis‐pyrene (BP) to construct a peptide–AIEgen hybrid nanosystem (PAHN). After intravenous injection, the versatile nanoplatform not only improved the hydrophilicity of BP but also achieved stratified targeting from tumor to mitochondrial and induced mitochondrial dysfunction, thus activating caspase‐3 upregulation. Then, sonodynamic therapy (SDT), an alternative modality with high tissue penetrability, is performed to evoke reactive oxygen species (ROS) generation for BP. More importantly, since the hydrophilic shell is separated from the nanosystem by the specific cleavage of caspase‐3, the resulting decrease in hydrophilicity induced tight self‐aggregation of PAHN residues in situ, further allowing more absorbed energy to be used for ROS generation under ultrasound irradiation and enhancing SDT efficacy. Moreover, severe oxidative stress resulting from ROS imbalance in the mitochondria initiates the immunogenic cell death process, thus evoking antitumor immunogenicity. This PAHN provides prospective ideas into AIE‐involved antitumor therapy and design of peptide‐AIEgens hybrids.