Record-High Ultrasound-Sensitive NO Nanogenerators for Cascade Tumor Pyroptosis and Immunotherapy

Pyroptosis is a pro-inflammatory cell death that is associated with innate immunity promotion against tumors. Excess nitric oxide (NO)-triggered nitric stress has potential to induce pyroptosis, but the precise delivery of NO is challenging. Ultrasound (US)-responsive NO production has dominant priority due to its deep penetration, low side effects, noninvasion, and local activation manner. In this work, US-sensitive NO donor N-methyl-N-nitrosoaniline (NMA) with thermodynamically favorable structure is selected and loaded into hyaluronic acid (HA)-modified hollow manganese dioxide nanoparticles (hMnO₂ NPs) to fabricate hMnO₂ @HA@NMA (MHN) nanogenerators (NGs). The obtained NGs have a record-high NO generation efficiency under US irradiation and can release Mn²⁺ after targeting the tumor sites. Later on, cascade tumor pyroptosis and cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING)-based immunotherapy is achieved and tumor growth is effectively inhibited.