Biodegradable Long-Circulating Nanoagonists Optimize Tumor-Tropism Chemo-Metalloimmunotherapy for Boosted Antitumor...

Area of Science:

• Nanotechnology
• Immunotherapy
• Oncology

Background:

• The cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) pathway is a promising target for inducing antitumor immunity.
• The tumor microenvironment (TME) often contains immunosuppressive cells that hinder the effectiveness of cGAS-STING pathway activation.
• Synergistic strategies are needed to overcome TME-mediated immunosuppression and enhance immunotherapeutic outcomes.

Purpose of the Study:

• To design biodegradable nanoparticles for synergistic chemo-metalloimmunotherapy.
• To achieve cascade activation of the cGAS-STING pathway for enhanced antitumor immunity.
• To develop a long-circulating, tumor-targeting nanoagonist for cancer treatment.

Main Methods:

• Fabrication of Mn-doped mesoporous silica (MM) nanoparticles with MOF gating and erythrocyte membrane (eM) camouflaging.
• Coloading of cisplatin (CDDP) and a STING agonist (SR-717) into the nanoparticles.
• In vitro and in vivo evaluation of nanoparticle-mediated drug release, cGAS-STING activation, and antitumor efficacy.

Main Results:

• The nanoparticles demonstrated controlled release of CDDP and SR-717 in response to tumor microenvironment stimuli.
• Released dsDNA fragments from cancer cells triggered cGAS-STING activation, promoting dendritic cell maturation and cytotoxic T cell infiltration.
• The synergistic chemo-metalloimmunotherapy resulted in significant tumor regression and enhanced antitumor immune responses.

Conclusions:

• Biodegradable, long-circulating nanoparticles effectively co-deliver chemotherapy and immunotherapy agents.
• Cascade cGAS-STING activation via nanotechnology offers a potent strategy for synergistic cancer treatment.
• This approach represents a paradigm shift in combining chemotherapy and metalloimmunotherapy for oncological applications.