Systemic Delivery of a STING Agonist‐Loaded Positively Charged Liposome Selectively Targets Tumor Immune Microenvironment and Suppresses Tumor Angiogenesis

Abstract

Although stimulator of interferon genes (STING) agonists has shown great promise in preclinical studies, the clinical development of STING agonist therapy is challenged by its limited systemic delivery. Here, positively charged fusogenic liposomes loaded with a STING agonist (PoSTING) are designed for systemic delivery and to preferentially target the tumor microenvironment. When PoSTING is administered intravenously, it selectively targets not only tumor cells but also immune and tumor endothelial cells (ECs). In particular, delivery of STING agonists to tumor ECs normalizes abnormal tumor vasculatures, induces intratumoral STING activation, and elicits robust anti‐tumor T cell immunity within the tumor microenvironment. Therefore, PoSTING can be used as a systemic delivery platform to overcome the limitations of using STING agonists in clinical trials.

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

“…In the same study, a stronger IFNβ response and higher weight loss upon either polySTING or free drug treatment was observed compared to healthy mice, likely due to inflammation in the tumor causing weight loss from ablation (Figure c,d compared with Figures S15 and S16). Weight loss increased with subsequent administration; however, it remained below 10% loss up to the third injection, a treatment regime comparable to many other reported systemic STING delivery platforms. ,, …”

“…In addition to the development of alternative small-molecule STING agonists, − multiple drug delivery platforms have been developed to address STING delivery challenges . Lipid micelles, polymersomes, , liposomes, , inorganic nanoparticles, or drug-conjugated polymeric particles have all been employed as systemic STING agonist carriers with potent responses.…”

Chemical Biology Perspectives on STING Agonists as Tumor Immunotherapy

“…[168] Liposomes exhibit low toxicity and immunogenicity, high biocompatibility, and component (phospholipid) biodegradabil-ity, thereby enhancing in vivo drug concentration while protecting drugs from degradation. [169] The versatility of these nanoparticles allows for facile modification with a wide range of ligands and functional molecules, making them suitable for targeted delivery of drugs and gene therapies. [170] Currently, many research teams are utilizing liposomes to deliver STING agonists in order to enhance innate immunity and antitumor effects.…”