Cholesterol-deficient T cell membrane-encapsulated STING agonists for tumor-targeted immunotherapy

In recent years, STING agonists have shown promising results in enhancing tumor immunotherapies. Nanoparticle-based tumor targeting delivery of STING agonists is considered as an important way to improve the therapeutic efficacy and reduce the side effects of STING agonists. However, how to escape the clearance to nanoparticles by phagocytes in the blood while maintaining the tumor targeting efficiency of nanoparticles is still a big challenge. Herein, cholesterol-deficient membrane from bioengineered T cells overexpressing PD-1 encapsulated STING agonist SR-717 (a.k.a. COMs) was used to treat melanoma. Nanoparticles coated by these membranes displayed remarkably dropped clearance by monocytes in the blood in both animal and human blood comparing with nanoparticles coated by non-modified T cell membrane, while maintaining the high tumor cell targeting efficiency of COMs. In mice melanoma model, intravenous injected COMs successfully delivered SR-717 to tumor and activated STING pathways and the PD-1 on COMs blocked the up-regulated PD-L1 in tumor cells induced by SR-717. As a result, COMs stimulated strong tumor immune responses to inhibit melanoma recurrence when it combined with photothermal therapy (PTT). In summary, this study developed a highly effective bionic system that integrated STING activation and immunotherapy, and provided a simple and effective strategy to enhance performance of cell membrane-coated delivery systems in vivo.