Manganese has recently been exploited for cancer immunotherapy, fenton-like reaction-mediated chemo-dynamic therapy, and magnetic resonance imaging. The integration of multiple roles of manganese into one platform is of great significance for cancer theranostics and tumor inhibition. Here, we designed a multifunctional nanoplatform based on manganese, which consisted of a manganese-containing inner core and a phospholipid bilayer shell co-loaded with glucose oxidase (GOx), paclitaxel (PTX), and a NIR fluorescent dye (NanoMn-GOx-PTX). In a pH-dependent manner, the nanoplatform released manganese ions and payloads inside the tumor cells. In vitro characterization and cellular experiments indicated that NanoMn-GOx-PTX could catalyze the conversion of glucose into reactive oxygen species (ROS) through a cascade Fenton-like reaction as well as release free PTX. The consumption of glucose, ROS production, and the chemotherapeutic effect of PTX contributed to the superior cytotoxicity and apoptosis of 4T1 cancer cells. Moreover, NanoMn-GOx-PTX effectively induced the production of large amounts of type I interferon and pro-inflammatory cytokines in vivo, activating the innate immune response. Through the synergistic functions of the above components, NanoMn-GOx-PTX exerted the strongest anti-tumor effect in 4T1 tumor-bearing models. Therefore, the manganese-based nanoplatform could serve as a promising theranostic tool for breast cancer therapy.

Statement of significance

1) This nanoplatform can be used as a universal tool for delivering proteins and anticancer drugs into cells; 2) The PEG-modified phospholipid bilayer shell plays a significant role in retarding the release of overloaded manganese ions and drugs in a pH-sensitive manner; 3) The released Mn²⁺ has the ability to enhance T1 contrast in magnetic resonance imaging; 4) The released Mn²⁺ can function as nanoadjuvants to activate the cGAS-STING pathway and effectively induce the natural immune response;5) The overloaded manganese ions are combined with glucose oxidase to form a cascade reaction system, indirectly converting glucose into ROS to induce oxidative damage of tumor tissue.