Metabolic Inhibitor Loaded Metal-Phenolic Nanocapsules Enable Synergistic Cancer Therapy through Cuproptosis and...

Area of Science:

• Biomedical Engineering
• Cancer Biology
• Nanotechnology

Background:

• Abnormal cellular metabolism, including glycolysis and glutamine metabolism, is a hallmark of cancer, fueling tumor growth and altering the tumor microenvironment (TME).
• Targeting single metabolic pathways often proves insufficient for effective cancer treatment due to compensatory mechanisms and low tumor immunogenicity.

Purpose of the Study:

• To develop novel dual-starvation therapeutic nanocapsules (CG@Cap) for simultaneous suppression of glycolysis and glutamine metabolism.
• To investigate the potential of CG@Cap in reprogramming the immunosuppressive TME and enhancing cancer immunotherapy.

Main Methods:

• Fabrication of metal-phenolic nanocapsules (CG@Cap) encapsulating a glutamine metabolism inhibitor and glucose oxidase, assembled with tannic acid and copper ions.
• Evaluation of CG@Cap's preferential accumulation, cellular uptake, and dual metabolic inhibition in tumor models.
• Assessment of TME remodeling, induction of cuproptosis, and antitumor immune response.

Main Results:

• CG@Cap successfully delivered and released cargo, simultaneously inhibiting glycolysis and glutamine metabolism in tumor cells.
• Dual metabolic suppression disrupted tumor energy supply and remodeled the immunosuppressive TME.
• Redox imbalance induced by CG@Cap enhanced copper-mediated cuproptosis, leading to a significant antitumor immune response and potent therapeutic efficacy in vivo.

Conclusions:

• Dual-starvation nanocapsules offer a promising strategy for cancer therapy by integrating immunometabolic reprogramming with cuproptosis induction.
• CG@Cap demonstrates significant therapeutic potential by simultaneously targeting tumor metabolism and eliciting an antitumor immune response.