Supramolecular Metallacycle Enables Esterase-Responsive and Endoplasmic Reticulum-Associated Pathway Activation for
Sina Chen1, Dongdong Xu1, Huanan Yu2
1Key Laboratory of Organosilicon Chemistry and Materials Technology of the Ministry of Education, Zhejiang Key Laboratory of Organosilicon Material Technology, College of Materials, Chemistry and Chemical Engineering, Hangzhou Normal University, Hangzhou 311121, P. R. China.
ACS Nano
|January 14, 2026
Summary
Researchers developed a novel supramolecular metallacycle nanoparticle that targets the endoplasmic reticulum for cancer immunotherapy. This platform activates the cGAS-STING pathway, enhancing immune responses for tumor ablation and metastasis suppression.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Research
Background:
- Supramolecular metallacycles offer potential for integrating cancer therapies.
- Activating the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is a promising immunotherapy strategy.
- The integration of metallacycles with cGAS-STING activation for cancer treatment remains underexplored.
Purpose of the Study:
- To engineer an endoplasmic reticulum (ER)-accumulating supramolecular platinum(II) metallacycle (M2) for esterase-responsive cGAS-STING activation.
- To develop a nanoplatform for synergistic photothermal immunotherapy by co-delivering a photothermal agent, a platinum(II) chemotherapeutic unit, and the STING agonist DMXAA.
- To investigate the potential of this nanoplatform for primary tumor ablation and suppression of distant metastases.
Main Methods:
- Fabrication of M2 supramolecular metallacycle nanoparticles (NPs) co-delivering therapeutic agents and DSPE-PEG for ER targeting.
- Utilizing caveolin-mediated endocytosis for selective NP accumulation in tumor ER.
- Investigating intracellular esterase-triggered NP disassembly and photothermal stimulation for DMXAA release and STING activation.
- Evaluating the synergistic effects of photothermal therapy and chemotherapy on immunogenic cell death and cGAS-STING signaling amplification.
Main Results:
- M2 NPs selectively accumulated in tumor ER via caveolin-mediated endocytosis.
- Intracellular esterase and photothermal stimulation triggered NP disassembly, releasing DMXAA to activate STING.
- Synergistic photothermal/chemotherapy induced immunogenic cell death, releasing DAMPs and generating dsDNA, further amplifying cGAS-STING signaling.
- The dual-pathway activation led to potent antitumor immunity, achieving primary tumor ablation and suppressing distant metastases in mouse models.
Conclusions:
- Supramolecular Pt(II) metallacycles can be engineered for targeted drug delivery and cGAS-STING pathway activation.
- This nanoplatform enables synergistic photothermal immunotherapy through dual-pathway cGAS-STING activation.
- The developed strategy holds significant potential for integrating photothermal therapy with immune-related functions in cancer treatment.
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