pH and Redox Dual-Responsive\nNanoparticle with Enhanced\nDendritic Cell Maturation for Cancer Therapy

Type I interferons (IFNs) are essential for activating\ndendritic\ncells (DCs) and presenting tumor-associated antigens to T cells. IFNs\nare primarily produced from DCs among immune cells. A combination\nof chemotherapy and metalloimmunotherapy induces IFN production by\nactivating the cyclic GMP-AMP synthase-stimulator of interferon genes\n(cGAS-STING) pathway. However, chemotherapeutic agents deplete DC\npopulations, suppressing immunostimulatory activities, despite their\npotent anticancer activities. Furthermore, an optimal ratio between\nchemotherapeutic agents and metal for activating DCs at the highest\nlevel has not been reported, and evidence for ensuring DC survival\nis lacking. In this study, we hypothesized that there is an optimal\nratio to yield the highest DC maturation and anticancer activity with\nminimal DC depletion. To demonstrate it, we have designed a pH and\nredox dual-responsive nanoparticle, MnO<sub>2</sub>@BSA@DOX (MD),\nto prevent DCs from depleting and activate the cGAS-STING pathway\nboth in cancer cells and DCs, inducing considerable levels of IFNs\nand maturation. MD consists of a core-layer structure, a manganese\ndioxide (MnO<sub>2</sub>) core, and a cross-linked layer with bovine\nserum albumin (BSA) and doxorubicin (DOX), with a specific ratio of\nDOX to manganese. MD exhibits structure-based selectivity between\ncancer cells and DCs by targeting the extracellular pH of the tumor\nmicroenvironment and intracellular redox reactions in cancer cells.\nAmong various formulations, the 1:1 ratio shows the highest maturation\nwith no significant depletion. Moreover, it induces distinct cytotoxicity\nin cancer cells through apoptosis and cGAS-STING activation, leading\nto increased calreticulin expression and enhanced DC phagocytosis.\nConsequently, it results in superior tumor suppression and prolonged\nsurvival with the high accumulation of MD in the tumor and no observed\nsystemic toxicities, highlighting its potential as a therapeutic agent\nin cancer treatments.