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

Abstract

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-<i>co</i>-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.