pH and Redox Dual-Responsive Nanoparticle with Enhanced Dendritic Cell Maturation for Cancer Therapy

Type I interferons (IFNs) are essential for activating dendritic cells (DCs) and presenting tumor-associated antigens to T cells. IFNs are primarily produced from DCs among immune cells. A combination of chemotherapy and metalloimmunotherapy induces IFN production by activating the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway. However, chemotherapeutic agents deplete DC populations, suppressing immunostimulatory activities, despite their potent anticancer activities. Furthermore, an optimal ratio between chemotherapeutic agents and metal for activating DCs at the highest level has not been reported, and evidence for ensuring DC survival is lacking. In this study, we hypothesized that there is an optimal ratio to yield the highest DC maturation and anticancer activity with minimal DC depletion. To demonstrate it, we have designed a pH and redox dual-responsive nanoparticle, MnO₂@BSA@DOX (MD), to prevent DCs from depleting and activate the cGAS-STING pathway both in cancer cells and DCs, inducing considerable levels of IFNs and maturation. MD consists of a core-layer structure, a manganese dioxide (MnO₂) core, and a cross-linked layer with bovine serum albumin (BSA) and doxorubicin (DOX), with a specific ratio of DOX to manganese. MD exhibits structure-based selectivity between cancer cells and DCs by targeting the extracellular pH of the tumor microenvironment and intracellular redox reactions in cancer cells. Among various formulations, the 1:1 ratio shows the highest maturation with no significant depletion. Moreover, it induces distinct cytotoxicity in cancer cells through apoptosis and cGAS-STING activation, leading to increased calreticulin expression and enhanced DC phagocytosis. Consequently, it results in superior tumor suppression and prolonged survival with the high accumulation of MD in the tumor and no observed systemic toxicities, highlighting its potential as a therapeutic agent in cancer treatments.