Abstract
Stimulator of interferon genes (STING) agonists have attracted notable attention for their potent immune activation capabilities. However, their clinical application is hindered by systemic toxicity and delivery inefficiencies. We addressed these challenges by developing a lymph node-targeted STING agonist nanoadjuvant (Mn/MSA-2@Lipo) combined with a temporally optimized delivery strategy. Mn/MSA-2@Lipo uses manganese ions to amplify STING pathway activation while achieving efficient lymph node accumulation and antigen presentation. We first induced immunogenic cell death (ICD) through chemotherapy to release tumor antigens, followed by the administration of the nanoadjuvant at an optimized time interval, the approach effectively synchronizes dendritic cell (DC) antigen uptake and maturation. This combination therapy notably enhanced antitumor immunity in melanoma and breast cancer models, achieving complete tumor regression and inducing long-lasting immune memory, all while demonstrating an excellent safety profile. Our findings highlight the critical importance of delivery timing optimization, offering a promising strategy for the clinical translation of STING agonists and the design of advanced immunotherapies.