Penetrate-Then-Gate Bioorthogonal In Situ Cancer Vaccination for Aligned Antigen Capture and Localized TLR7/8...

Area of Science:

• Biotechnology
• Immunology
• Materials Science

Background:

• In situ cancer vaccination faces challenges with antigen diffusion, systemic adjuvant effects, and mistimed immune responses.
• Current methods struggle to precisely control the spatiotemporal delivery of antigens and adjuvants within tumors.

Purpose of the Study:

• To develop a "penetrate-then-gate" nanoparticle system for precise in situ cancer vaccination.
• To decouple the distribution and activation of therapeutic agents for improved immunotherapy.

Main Methods:

• Intravenous administration of poly(propylene sulfide) (PPS) nanoparticles (∼25 nm) for tumor penetration.
• Near-infrared irradiation to trigger photosensitizer (PPa)-induced oxidation of PPS to poly(propylene sulfone) (PPSU).
• In situ assembly of PPSU network to capture endogenous antigens and co-localize with TLR7/8 agonist (IMDQ).

Main Results:

• Optical imaging confirmed earlier and sustained intratumoral drug exposure with coadministration compared to sequential dosing.
• Improved primary tumor control, enhanced rechallenge protection, and suppressed distant tumor growth in multiple cancer models.
• Minimized systemic cytokine release, indicating localized therapeutic action.

Conclusions:

• The "penetrate-then-gate" design effectively aligns antigen availability with immune licensing for precise in situ cancer vaccination.
• This modular approach offers a spatiotemporal strategy for durable and effective tumor immunotherapy with reduced systemic toxicity.