Cholesterol removal significantly improves performance of a model anti-tumor biomimetic nano delivery system integrating immunotherapy and STING activation

Abstract Biomimetic drug delivery systems have attracted much interests as they could accomplish tasks such as precise delivery and biological barrier penetration. Biological membranes often play important functional roles in these systems. We discover that the circulating time and targeting capability of biological membrane-coated nanovehicles could be significantly improved by reducing their cholesterol content with simple (2-hydroxypropyl)-β-cyclodextrin treatment. A proof-of-concept biomimetic nano system using cholesterol-reduced T cell membrane with overexpressed PD-1 to deliver photothermal agent and STING agonist SR-717 is fabricated and assessed. Comparing with non-modified membrane and conventional PEGlaytion modified membranes, these membranes offer remarkably improved performance in immunocompetent mice, with ~ 2-fold increase in tumor accumulation. After intravenous injection and laser irradiation, melanoma tumors are completely eliminated with no recurrence for > 100 days in > 80% treated mice. Mechanistic studies suggest that the treated membranes could efficiently escape the immune surveillance to avoid blood clearance while keeping functional surface molecules exposed. This subtractive strategy does not introduce new substances and appears to be highly safe. In summary, we discover a simple, safe and widely-applicable biological membrane modification strategy that could significantly improve delivery performance. This strategy displays advantages than conventional PEGlaytion in some aspects and has good potential for further development.