Controlling intracellular processing to enhance spherical nucleic acid immune stimulation.

Area of Science:

• Immunology
• Nanotechnology
• Vaccine Development

Background:

• Effective vaccines require efficient intracellular antigen processing for robust immune responses.
• Endoplasmic reticulum aminopeptidase 1 (ERAP1) plays a crucial role in generating MHC class I epitopes.

Purpose of the Study:

• To develop and evaluate a modular approach using spherical nucleic acid (SNA) nanostructures to optimize antigen processing pathways.
• To design ERAP1-responsive peptide linkers (EPLs) to control antigen processing efficiency and bias towards ERAP1.

Main Methods:

• Spherical nucleic acid (SNA) nanostructures were engineered with two distinct ERAP1-responsive peptide linkers (EPLs).
• The substrate specificity of ERAP1 was utilized to append peptide antigens to SNAs.
• Antigen processing efficiency, colocalization with ERAP1, antigen surface presentation, T cell responses, and in vivo tumor inhibition were measured.

Main Results:

• The two EPLs modulated ERAP1 antigen processing efficiency by up to 10-fold.
• Antigen colocalization with ERAP1 increased by approximately 58% with EPLs.
• Enhanced antigen processing via EPLs led to increased antigen presentation, CD8+ T cell proliferation, and generation of proinflammatory and effector memory T cells.
• SNA nanostructures with more efficient EPLs demonstrated a 2.5-fold greater inhibition of lymphoma tumors in vivo.

Conclusions:

• Deliberate design of vaccine structures, such as SNA nanostructures with EPLs, can spatially bias antigen processing.
• Optimizing antigen processing efficiency is critical for augmenting immune stimulation and enhancing vaccine efficacy.
• This approach holds promise for developing next-generation vaccines with improved therapeutic outcomes.