Ca2+-driven self-amplified nanoplatform targeting ER-mitochondrial calcium crosstalk for synergistic apoptosis induction and tumor immune microenvironment remodeling.

Breast cancer chemotherapy faces severe limitations due to multidrug resistance and metastasis. Herein, we report a rationally designed ORI-LDH@LP (OLL) nanoplatform that establishes a self-reinforcing vicious cycle among endoplasmic reticulum (ER) stress, mitochondrial calcium overload, and oxidative stress to drive irreversible tumor cell apoptosis and reshape the immunosuppressive tumor microenvironment. This nanoplatform comprises oridonin-loaded Mn2+-based layered double hydroxides encapsulated within folate-targeting liposomes. Upon internalization, released oridonin triggers intense ER stress, activating the PERK-eIF2α-ATF4-CHOP axis and upregulating the IP3R-GRP75-VDAC complex at mitochondria-associated ER membranes to facilitate massive Ca2+ flux into mitochondria. This targeted calcium overload induces mitochondrial permeability transition pore opening, membrane potential collapse, ATP depletion, and reactive oxygen species (ROS) burst. Concurrently, released Mn2+ catalyzes hydroxyl radical generation via Fenton-like reactions, synergistically amplifying oxidative damage. This interplay between ER stress-mediated calcium signaling and Mn2+-catalyzed ROS generation creates a self-amplifying cascade that drives mitochondrial-dependent apoptosis. Beyond direct cytotoxicity, the ROS storm triggers immunogenic cell death, while Mn2+ robustly activates the cGAS-STING pathway, establishing a positive feedback loop that amplifies innate immune signaling. This dual mechanism promotes type I interferon production, driving tumor-associated macrophage repolarization from the protumoral M2 to the antitumoral M1 phenotype and enhancing cytotoxic T lymphocyte infiltration. In 4T1 tumor-bearing mice, OLL achieved remarkable tumor suppression without systemic toxicity, demonstrating potent antitumor efficacy through combined direct killing and systemic immune activation. This study establishes a nanomaterial-driven paradigm for precisely modulating ER-mitochondria crosstalk to overcome drug resistance and ignite antitumor immunity, offering a promising strategy for cancer nanotherapeutics.