Enhancing tumor immunotherapy with smart nanoparticles for reprogramming macrophages and blocking the CD47/Sirpα...

Area of Science:

• Biomedical Engineering
• Nanotechnology
• Immunology

Background:

• Immunotherapy faces challenges due to immunosuppressive tumor immune microenvironments (TIME).
• Tumor-associated macrophages (TAMs), especially M2-like, promote tumor growth and immune evasion.
• Targeting TAMs is crucial for enhancing cancer treatment efficacy.

Purpose of the Study:

• To develop novel dual-targeted nanoparticles (ZrMOF/C@P) for modulating TAMs.
• To investigate the efficacy of STING agonist-loaded nanoparticles in reprogramming TAMs.
• To evaluate the therapeutic potential of these nanoparticles in solid tumor models.

Main Methods:

• Synthesis of enzyme-responsive, cell membrane-coated nanoparticles (ZrMOF/C@P).
• Loading nanoparticles with 2', 3'-cGAMP (STING agonist) and targeting peptides (Pep20, MMP2, M2pep).
• In vitro studies on macrophage reprogramming and in vivo evaluation in CT26 and 4T1 tumor models.

Main Results:

• Nanoparticles successfully reprogrammed M2-like TAMs to M1-like phenotypes by activating the STING pathway.
• Smart ZrMOF/C@P demonstrated prolonged tumor accumulation.
• Significant tumor growth suppression and enhanced systemic anti-tumor immunity, including increased CD8+ T cell infiltration and IFN-γ secretion.

Conclusions:

• Smart ZrMOF/C@P nanoparticles offer a promising strategy to overcome TIME immunosuppression.
• This approach represents a novel method for systemic administration of non-CDN-STING agonists.
• The engineered nanoparticles provide a versatile and effective treatment for solid tumors.