Nano‐Enabled Systemic Delivery of STING Agonist by Engineered Silicasome for Potent Antitumor Immunotherapy

ABSTRACT Activation of the STING pathway represents a potent strategy for cancer immunotherapy. However, the instability and systemic toxicity of STING agonists, especially cyclic dinucleotides (CDNs), limit their use via local administration with poor efficacy against metastatic or inaccessible tumors. Here, we develop an engineered silicasome nanocarrier for systemic delivery of the CDN ADU‐S100 (ADU‐Sili). Comprising ADU‐S100‐loaded mesoporous silica nanoparticles (MSNPs) coated with lipid bilayer, ADU‐Sili markedly enhanced tumor accumulation and antitumor efficacy compared with free ADU‐S100 and conventional liposomes in vivo. The advantage of systemic delivery was further demonstrated in bilateral tumors: ADU‐Sili induced systemic antitumor immunity, suppressing both tumors, whereas free ADU‐S100 inhibited only injected tumors. Immune profiling revealed that ADU‐Sili promoted dendritic cell maturation in lymph nodes, expanded cytotoxic and memory CD8 ⁺ T cells in spleens, elevated intratumoral effector cytokines, and polarized tumor‐associated macrophages toward an M1 phenotype. Notably, combining ADU‐Sili with immune checkpoint blockade (ICB) synergistically enhanced antitumor efficacy as demonstrated in more clinically relevant orthotopic tumor models. In summary, silicasomes enable effective systemic CDN delivery, eliciting robust immune and antitumor responses and overcoming intratumoral delivery limitations in STING‐based cancer immunotherapy.