Reprogramming anti-tumor immunity through both NLRP3 inflammasome and cGAS-STING pathways by chiral nanoadjuvants

Area of Science:

• Nanotechnology
• Immunology
• Materials Science

Background:

• Cancer immunotherapy faces challenges including safety concerns, the tumor microenvironment, and low immunogenicity of cancer vaccines.
• Developing novel vaccine strategies with improved efficacy and safety is crucial for advancing cancer treatment.

Purpose of the Study:

• To synthesize degradable chiral trimanganese tetroxide nanoparticles (Mn3O4 NPs) using chiral mannose ligands for cancer therapy and prevention.
• To investigate the uptake mechanisms, immune activation pathways, and anti-tumor efficacy of these novel chiral vaccines.

Main Methods:

• Synthesis of L-type and D-type Mn3O4 nanoparticles (NPs) modified with chiral mannose ligands.
• Assessment of nanoparticle uptake by mouse bone marrow dendritic cells (BMDCs) and their affinity for XCR1, CD14, and TLR4.
• Evaluation of BMDC activation via NLRP3 inflammasome and cGAS-STING pathways, cytokine expression analysis (CCL5, CCL22), and molecular dynamics simulations.
• In vivo testing of chiral vaccines (L-Vac) in a patient-derived xenograft (PDX) mouse model for anti-tumor immunity and biosafety.

Main Results:

• L-type Mn3O4 NPs (L-NPs) demonstrated nearly double the uptake rate in BMDCs compared to D-type NPs, attributed to higher affinity for XCR1, CD14, and TLR4.
• L-Vac activated BMDCs through NLRP3 inflammasome and cGAS-STING pathways, increasing CCL5 and decreasing CCL22 levels.
• Molecular dynamics simulations revealed a lock-and-key mechanism in chiral NP-antigen interactions.
• Significant anti-tumor immunity was confirmed in a PDX mouse model, and L-Vac showed high in vivo biosafety with manganese ions primarily excreted via feces.

Conclusions:

• Degradable chiral Mn3O4 NPs, particularly L-NPs, serve as effective chiral vaccines (L-Vac) for cancer therapy and prevention.
• Chiral vaccines enhance anti-tumor immunity by modulating dendritic cell activation and cytokine profiles.
• The demonstrated in vivo biosafety and efficacy highlight the clinical potential of chiral adjuvants in advancing cancer immunotherapy.