Genetically programmed engineered nanodevices trigger cascade reinforcement between AMPK and cGAS-STING activation...

Area of Science:

• Nanomedicine
• Cancer Immunotherapy
• Molecular Biology

Background:

• Colorectal cancer (CRC) immunotherapy is challenging due to an immunosuppressive tumor microenvironment (TME).
• Key TME factors include dysregulated CD47/SIRPα and PD-1/PD-L1 pathways, T cell exhaustion, and immunosuppressive cells.
• Novel strategies are needed to effectively reshape the TME for improved CRC treatment.

Purpose of the Study:

• To develop bioinspired nanodevices (SPCM@DMgTi-ADM) for enhancing colorectal cancer immunotherapy.
• To investigate the synergistic effects of blocking immune checkpoints, sonodynamic therapy, and ferroptosis induction.
• To create a self-amplifying loop of anti-tumor immunity.

Main Methods:

• Development of dendritic titanium-magnesium nanoparticles (DMgTi) as sonosensitizers and drug carriers for aldometanib (ADM).
• Coating nanoparticles with engineered membranes displaying SIRPα and PD-1 decoy receptors (SPCM) to block immune checkpoints.
• Utilizing released Mg2+ to enhance CD8+ T cell infiltration and cytotoxic function.
• Inducing autophagy-dependent ferroptosis via ADM and sonodynamic therapy (SDT) to trigger immunogenic cell death (ICD).
• Activating the cGAS-STING pathway through released dsDNA to sustain ferroptosis and boost anti-tumor immunity.

Main Results:

• The nanodevice effectively reshaped the TME by blocking CD47/SIRPα and PD-1/PD-L1 pathways.
• Synergistic therapy involving ADM, SDT, and ferroptosis induced potent immunogenic cell death (ICD).
• A self-amplifying loop was established where ferroptosis promoted dsDNA release, activating cGAS-STING, which in turn enhanced ferroptosis and anti-tumor immunity.
• In vitro and in vivo studies demonstrated effective tumor evaluation and activation of systemic anti-tumor immunity.

Conclusions:

• The developed bioinspired nanodevices offer a promising strategy for colorectal cancer immunotherapy.
• The synergistic approach effectively reshapes the tumor microenvironment and enhances anti-tumor immune responses.
• This clinically translatable strategy holds potential for precision therapy in colorectal cancer.