Genetically programmed engineered nanodevices trigger cascade reinforcement between AMPK and cGAS-STING activation for colon cancer sonoimmunotherapy.

Abstract

Immune checkpoint blockade (ICB) has shown clinical promise in cancer immunotherapy, but colorectal cancer (CRC) remains difficult to treat due to a complex immunosuppressive tumor microenvironment (TME). This TME features dysregulated CD47/SIRPα and PD-1/PD-L1 pathways, T cell exhaustion, and infiltration of immunosuppressive cells. Therefore, novel strategies to reshape TME are critically needed. Here we developed bioinspired nanodevices (SPCM@DMgTi-ADM) for CRC immunotherapy. These nanodevices consist of dendritic titanium-magnesium nanoparticles (DMgTi) that serve as both a sonosensitizer and a carrier for aldometanib (ADM). The nanoparticles are coated with genetically engineered membranes displaying SIRPα and PD-1 decoy receptors (SPCM). This design achieves cascade reinforcement between AMP-activated protein kinase (AMPK) activation and cGAS-STING activation. The SPCM coating simultaneously blocks SIRPα/CD47 and PD-1/PD-L1 axes, preliminarily reshaping the TME. Released Mg²⁺ induces conformational changes in LFA-1 on CD8⁺ T cells, promoting their tumor infiltration and cytotoxic function. ADM together with sonodynamic therapy (SDT) induces AMPK activation, which drives autophagy-dependent ferroptosis. This synergistic process triggers strong Immunogenic cell death (ICD). The released dsDNA potently activates the cGAS-STING, which in turn inhibits GPX4 and sustains ferroptotic stress. This creates a self-amplifying loop: ferroptosis promotes dsDNA release, which activates cGAS-STING; STING then suppresses GPX4, worsens ferroptosis and further boosting anti-tumor immunity. Both in vitro and in vivo studies confirm that our nanodevice effectively evaluates tumors and activates systemic anti-tumor immunity, offering a clinically translatable strategy for precision CRC therapy.