Cholesterol removal improves performance of a model biomimetic system to co-deliver a photothermal agent and a STING agonist for cancer immunotherapy

Biological membranes often play important functional roles in biomimetic drug delivery systems. We discover that the circulation time and targeting capability of biological membrane coated nanovehicles can be significantly improved by reducing cholesterol level in the coating membrane. A proof-of-concept system using cholesterol-reduced and PD-1-overexpressed T cell membrane to deliver a photothermal agent and a STING agonist is thus fabricated. Comparing with normal membrane, this engineered membrane increases tumor accumulation by ~2-fold. In a melanoma model in male mice, tumors are eliminated with no recurrence in >80% mice after intravenous injection and laser irradiation; while in a colon cancer model in male mice, ~40% mice are cured without laser irradiation. Data suggest that the engineered membranes escape immune surveillance to avoid blood clearance while keeping functional surface molecules exposed. In summary, we develop a simple, effective, safe and widely-applicable biological membrane modification strategy. This “subtractive” strategy displays some advantages and is worth further development. Strategies for biological membrane engineering have been proposed to enhance their anti-clearance efficiency and improve their clinical translation potential. Here the authors design nanoparticles coated with low-cholesterol membranes from T cells overexpressing PD1, showing reduced clearance in the blood and improved anti-tumor efficacy when loaded with a STING agonist and a photothermal agent.