Tumor-microenvironment-driven carbon-center radical generation accompanied by glutathione exhaustion for intensified...

The high redox levels within tumors position chemodynamic therapy (CDT) as a promising therapeutic approach. However, the CDT efficiency of dihydroartemisinin (DHA) is limited by rapid clearance from bloodstream, along with inadequate endogenous ferrous ions within tumor microenvironment and heightened anti-oxidative defense inside tumor cells. To overcome these limitations, we developed an innovative virus-like hollow mesoporous manganese nanocage, loaded with DHA and subsequently cloaked with red cell membrane, designed to trigger a tumor-microenvironment-responsive free radical generation, synergized with glutathione (GSH) exhaustion for enhanced CDT efficacy. Upon accumulation in tumor tissues via the enhanced penetration and retention (EPR) effect, the high concentration of GSH in cancer cells initiates the degradation of the nanocages. This process specifically and efficiently released both Mn²⁺ and DHA while simultaneously depleting GSH. The released Mn²⁺ further catalyzed the conversion of DHA to generate large amounts of highly toxic carbon-center (•C) radicals accompanied by the generation of Mn⁴⁺. The •C radical generation led to severe mitochondria dysfunction and DNA damage, potentially causing cancer cell death. The concurrently generated Mn⁴⁺ continued to depelete intracellular GSH and induce lipid peroxidation, thereby weakening cancer cells' anti-oxidative defenses and amplifing oxidative stress. The viability of 4T1 cells treated with DHA@vhmMN@RM was significantly lower (about 30 %) than other groups. This work presents a novel nanosystem that specifically enhances the therapeutic effect of CDT by leveraging a tumor microenvironment-responsive free radical generation, coupled with GSH exhaustion, offering a new avenue for targeted drug delivery and synergistic cancer therapy.