Dual-receptor targeting of type I dendritic cells with DNA-scaffolded nanoparticles enhances STING-licensed antitumor immunity

Activating the stimulator of interferon genes (STING) pathway in conventional type I dendritic cells (cDC1s) is crucial for inhibiting solid tumor metastasis. A major hurdle is the cell type–specific delivery of immune agonists. To overcome this, we created a DNA-scaffolded poly(lactic- co -glycolic acid) nanoparticle platform for precisely loading antibodies targeting cDC1 receptors, specifically DEC205 and Clec9A. Optimizing these targeting ligands revealed a 1:1 ratio as ideal for preferentially targeting splenic cDC1s in vivo. When the STING agonist MSA-2 was delivered via this platform, termed programmable and ratiometrically-engineered immunomodulatory nanoparticle (PRIME NP), its immunostimulatory activity significantly increased. In CT26 tumor–bearing mice, PRIME NP treatment triggered robust proinflammatory signaling and activated both innate and adaptive immune responses, leading to potent CD8 + T cell–driven tumor regression and long-term survival in preclinical models. This work provides a framework for designing actively targeted particles and emphasizes DNA-scaffolded nanoparticles as an effective strategy to enhance the STING-cDC1 pathway for solid tumor treatment.