Intraparticle Double-Scattering-Decoded Sonogenetics for Augmenting Immune Checkpoint Blockade and CAR-T Therapy

Area of Science:

• Biomedical Engineering
• Immunotherapy
• Nanotechnology

Background:

• Chimeric antigen receptor (CAR)-T cell therapy faces challenges in solid tumors, including poor infiltration, immunosuppressive tumor microenvironment (ITM), and insufficient immune cells.
• These hurdles limit the effectiveness of CAR-T and immune checkpoint blockade (ICB) immunotherapies.
• Overcoming these barriers is crucial for advancing cancer treatment.

Purpose of the Study:

• To develop a sonoimmunity-engineered nanoplatform to address the limitations of CAR-T immunotherapy in solid tumors.
• To enhance T cell infiltration, overcome the immunosuppressive tumor microenvironment, and boost anti-tumor immune responses.
• To improve the efficacy of CAR-T and ICB therapies against solid tumors.

Main Methods:

• A rattle-type nanoplatform was engineered to generate reactive oxygen species (ROS) via sonodynamic processes, utilizing intraparticle-double-scattering.
• The nanoplatform co-loaded phosphodiesterase-5 inhibitors to release nitric oxide (NO) for vascular normalization and opening the infiltration barrier (IB).
• Evaluated the nanoplatform's ability to kill tumor cells, release antigens, activate immune responses, polarize macrophages, and reduce pro-tumorigenic cytokines.

Main Results:

• The nanoplatform successfully generated massive ROS, leading to direct tumor cell killing and antigen release.
• It effectively alleviated the immunosuppressive tumor microenvironment by modulating macrophage polarization and reducing immunosuppressive cytokines.
• Nitric oxide release promoted vascular normalization and enhanced T cell infiltration into tumors, significantly improving CAR-T and ICB therapy outcomes and repressing metastasis.

Conclusions:

• The sonoimmunity-engineered nanoplatform demonstrates a feasible strategy for overcoming major hurdles in solid tumor immunotherapy.
• Intraparticle-double-scattering-decoded sonogenetics effectively expands effector T or CAR-T cells, promoting tumor infiltration and overcoming ITM.
• This approach significantly enhances CAR-T and ICB immunotherapies, offering a promising avenue for treating solid tumors and preventing metastasis.