Ultrasound-glutathione dual-responsive bionic nanoparticles activate STING-mediated cancer immunotherapy by inducing oxidative stress storm

As a non-invasive treatment method, sonodynamic therapy (SDT) has been proven to enhance immune system activity by inducing the generation of reactive oxygen species (ROS). However, the efficacy is constrained by the hypoxic tumor microenvironment (TME) and their intrinsic antioxidant defense mechanisms. To overcome these challenges, we have developed a manganese-based nanoplatform named HMAS@MH, which is responsive to both ultrasound and TME. This nanoplatform utilizes hollow mesoporous manganese dioxide (HM) as a carrier, loaded with oxygen-independent alkyl radical generator AIPH and siNrf2, and coated with hyaluronic acid (HA)-modified erythrocyte membrane (eM). After systemic administration, HMAS@MH preferentially accumulates in tumor regions, benefiting from the extended circulation time afforded by the eM camouflage and the active targeting ability conferred by HA. Under dual stimulation from exogenous ultrasound irradiation and endogenous conditions of low pH and high glutathione (GSH) levels, HMAS@MH decomposes to generate alkyl and hydroxyl radicals, resulting in the accumulation of cytoplasmic double-stranded DNA (dsDNA). Additionally, siNrf2 and Mn 2+ significantly blocks the neutralization of free radicals by inhibiting the antioxidant defense system and depleting GSH. As a non-cyclic dinucleotide stimulator of interferon genes (STING) agonist, Mn 2+ significantly enhances the sensitivity of cyclic GMP-AMP synthase (cGAS) protein to dsDNA, thereby activating the cGAS-STING pathway and triggering robust anti-tumor immune responses. In conclusion, this sonochemical therapy, combined with Nrf2 silencing, amplifies oxidative damage in tumor cells and boosts anti-tumor immunity, resulting in significant tumor suppression.