Tumor microenvironment-responsive delivery nanosystems reverse immunosuppression for enhanced CO gas/immunotherapy

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Cancer Research

Background:

• Carbon monoxide (CO) gas therapy shows promise for cancer treatment by inducing apoptosis and antitumor immunity.
• The immunosuppressive tumor microenvironment (TME) limits the therapeutic efficacy of CO therapy.
• Nanomaterials offer potential for targeted drug delivery and TME modulation.

Purpose of the Study:

• To develop a novel hollow-structured nanoplatform for enhanced CO delivery and TME modulation.
• To investigate the immunomodulatory properties of the nanoplatform for cancer immunotherapy.
• To combine CO therapy with immune checkpoint blockade for synergistic antitumor effects.

Main Methods:

• Fabrication of hollow rough MnO2 nanoparticles (RMH) encapsulating a CO prodrug and functionalized with hyaluronic acid (HA).
• Evaluation of RMH's ability to induce dendritic cell maturation and M1 macrophage polarization via STING pathway activation and hypoxia alleviation.
• Assessment of TME-responsive CO release and combination therapy with anti-PD-L1 in a tumor model.

Main Results:

• The M-RMH nanosystems demonstrated enhanced cellular uptake and TME-responsive degradation.
• RMH effectively promoted dendritic cell maturation and M1 macrophage polarization, alleviating tumor hypoxia.
• Combined CO therapy and anti-PD-L1 immunotherapy significantly inhibited primary and distant tumor growth.

Conclusions:

• The developed hollow nanoplatform (M-RMH) is an effective strategy for TME modulation and enhanced CO/immunotherapy.
• This approach activates antitumor immunity and reverses immunosuppression, offering a promising avenue for cancer treatment.
• Morphological optimization and intrinsic properties of nanomaterials are crucial for synergistic cancer therapy.