Acid-degradable hollow calcium-manganese nanocarriers integrate calcium stress, redox catalysis, and antitumor immunity for lung cancer therapy.

Abstract

Non-small cell lung cancer (NSCLC) remains a major cause of cancer-related mortality, while acquired resistance to EGFR-targeted therapy and an immunosuppressive tumor microenvironment continue to limit therapeutic efficacy. Here, we developed a tumor cell membrane-coated, acid-degradable hollow calcium-manganese nanoplatform loaded with gefitinib (CM@HCC-Mn/Gef) for combined redox modulation and antitumor immune activation. Under acidic and redox-active conditions, CM@HCC-Mn/Gef released gefitinib, Ca2+, and Mn2+, leading to intracellular Ca2+ accumulation, mitochondrial depolarization, ATP depletion, reactive oxygen species generation, glutathione consumption, GPX4 downregulation, and lipid peroxidation. These coordinated effects induced ferroptosis-associated oxidative damage and immunogenic cell death (ICD), characterized by cell-surface calreticulin exposure and HMGB1 redistribution, and subsequently promoted dendritic cell maturation and T-cell activation. In gefitinib-resistant NSCLC cells, CM@HCC-Mn/Gef produced substantially greater cytotoxicity than free gefitinib, indicating that multimechanistic stress amplification enhanced the therapeutic response of resistant tumor cells. In immunocompetent syngeneic LLC tumor models, the nanoplatform inhibited primary tumor growth, increased tumor-infiltrating T cells, alleviated immunosuppressive features of the tumor microenvironment, and delayed contralateral secondary tumor progression. Combination with anti-PD-1 further enhanced tumor suppression and systemic immune activation. Collectively, CM@HCC-Mn/Gef integrates targeted drug delivery, calcium-associated mitochondrial stress, redox disruption, ferroptosis-associated damage, and immune activation, providing a biomimetic nanotherapeutic strategy for NSCLC chemoimmunotherapy. STATEMENT OF SIGNIFICANCE: Conventional nanocarriers often provide drug delivery without coordinating multiple tumor-specific stresses and immune activation. This study introduces a tumor cell membrane-coated, acid-degradable hollow calcium-manganese nanoplatform that co-releases gefitinib, Ca2+, and Mn2+ in the tumor microenvironment. The material couples calcium-associated mitochondrial dysfunction with manganese-driven redox catalysis, thereby enhancing oxidative damage, lipid peroxidation, and immunogenic cell death-associated responses. It also improves tumor accumulation, promotes dendritic cell maturation and T-cell activation, and enhances anti-PD-1 therapy in immunocompetent lung cancer models. This work establishes a direct link between biomaterial composition, stimulus-responsive degradation, catalytic function, and antitumor immunity, offering a versatile design strategy for biomaterials-enabled chemoimmunotherapy.