Biodegradable hollow MnO2 decorated by carbon dots with cholesterol depletion capability for cascaded amplification of sono-immunotherapy

Abstract

For the effective activation of the adaptive immune response, it is crucial to promote the maturation of dendritic cells (DCs) and subsequently initiate cytotoxic T lymphocytes. Nevertheless, the immunosuppressive tumor microenvironments (TME) are believed to hinder DC maturation, leading to a significant decrease in the effectiveness of immunotherapy. In this work, we present the first instance of combining ROS-triggered immunogenic cell death (ICD), cholesterol depletion, and STING activation to achieve the cascade amplification of antitumor immune response. The Zr-based metal-organic frameworks (MOF) is utilized as the template for the synthesis of hollow MnO₂ (H–MnO₂). Carbon dots (CDs) with cholesterol depletion capability are then deposited on H–MnO₂ to form heterojunctions. CD@H–MnO₂ not only has improved ROS generation ability under ultrasound due to heterojunction construction, but also shows GSH-responsive degradation properties, enabling the targeted release of CDs and Mn ions in tumors. CD@H–MnO₂-triggered cascade amplification of antitumor immune response is elucidated as follows: (1) Heterojunction construction, GSH depletion, and relief of hypoxia co-augmented ROS yield could significantly induce a robust ICD effect. (2) The released Mn ions stimulate DC maturation by activating the cGAS-STING pathway. (3) Direct enhancement of T cell toxicity can be realized by CDs through depleting cholesterol. Notable antitumor effects have been observed to eliminate primary tumors and stop the growth of distant tumors. This study presents a novel method to merge ROS-triggered ICD, cholesterol depletion, and STING activation into one nanomaterial to produce long-lasting and powerful immune responses.