Target Reprogramming Lysosomes of CD8+ T Cells by a Mineralized Metal-Organic Framework for Cancer Immunotherapy

Area of Science:

• Biotechnology
• Immunotherapy
• Nanomedicine

Background:

• T cell immunotherapy faces challenges in solid tumors due to low T cell activation and reduced therapeutic protein release.
• Key therapeutic proteins like perforin and granzyme B are sequestered within lysosomes, limiting their efficacy.
• Lysosomal targeting is crucial for enhancing T cell-mediated antitumor activity.

Purpose of the Study:

• To develop a novel lysosome-targeting nanoparticle (LYS-NP) for enhanced T cell immunotherapy.
• To improve the delivery and release of therapeutic proteins (perforin and granzyme B) within T cells.
• To enhance the antitumor effects of T cells against solid tumors, specifically breast cancer.

Main Methods:

• A metal-organic framework (MOF) was synthesized using Zn2+ and dimethylimidazole for protein encapsulation and acid sensitivity.
• Calcium carbonate (CaCO3) was used for MOF mineralization, enhancing stability and providing synergistic calcium ions.
• Therapeutic proteins (perforin and granzyme B) were preloaded into the MOF, and T cells were pretreated with tumor-specific antigens before LYS-NP recombination.

Main Results:

• The developed LYS-NP effectively targets lysosomes and enhances the release of therapeutic proteins.
• Mineralization with CaCO3 improved the stability of protein encapsulation within the MOF.
• T cells recombined with LYS-NPs demonstrated a significant enhancement in controlling breast cancer growth.

Conclusions:

• Lysosome-targeting nanoparticles offer a promising strategy to overcome T cell immunotherapy limitations in solid tumors.
• The MOF-based LYS-NP system facilitates efficient delivery and release of cytotoxic proteins, boosting T cell antitumor activity.
• This approach shows significant potential for improving cancer treatment outcomes, particularly in breast cancer.