Gradient Zinc-Doping Strategy Combined With Tumor Metabolic Interference for Effective Catalytic Immunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Immunotherapy

Background:

• Photocatalytic immunotherapy offers high selectivity and low side effects but faces challenges with light penetration and the immunosuppressive tumor microenvironment (TME).
• Poor tissue penetration of UV-Vis light and low energy of near-infrared (NIR) photons limit efficacy.
• The immunosuppressive TME hinders efficient catalytic activity and immune activation.

Purpose of the Study:

• To design a novel gradient Zn2+-doping polymeric carbon nitride (PCN) nanocatalyst (gZn-PCN@M) for enhanced NIR-triggered photocatalytic immunotherapy.
• To improve the penetration depth of nanomedicines into tumors.
• To combine metabolic interference with photocatalysis for efficient tumor treatment.

Main Methods:

• Synthesized gradient Zn2+-doped PCN (gZn-PCN@M) with decreasing Zn2+ concentration from interior to surface.
• Utilized 808 nm laser irradiation to trigger H2O decomposition and hydrogen gas production in the TME.
• Investigated Zn2+ release, reactive oxygen species (ROS) generation, tumor metabolism disruption, PD-L1 downregulation, and antitumor immune responses.

Main Results:

• gZn-PCN@M demonstrated enhanced penetration depth into tumors due to hydrogen gas generation.
• Acidic TME and laser irradiation promoted Zn2+ release, leading to elevated intracellular Zn2+ levels.
• This triggered ROS bursts, disrupted tumor energy metabolism, downregulated PD-L1, and activated antitumor immunity.
• Achieved high inhibition rates of 96.51% for primary tumors and 83.69% for distant tumors.

Conclusions:

• Gradient ion-doping is a novel strategy to enhance NIR responsiveness in photocatalytic nanomedicines.
• Combined metabolic interference with photocatalysis effectively treats tumors.
• gZn-PCN@M shows significant potential for efficient tumor photocatalytic immunotherapy.