Bioinspired Engineered Virus‐Mimetic Vesicles for Enhanced Cytosolic Delivery of STING Agonists Into Dendritic Cells

ABSTRACT Effective delivery to dendritic cells (DCs) is crucial for the clinical translation of STING agonists, however, current cyclic dinucleotide (CDN) therapies are hindered by inefficient cytosolic delivery and off‐target activation‐induced T cell exhaustion. Here, a high‐fidelity, dengue virus‐mimetic platform (CDN@VLP) is engineered to leverage natural tropism for precise cytosolic release in immature DCs. Compared to conventional lipid nanoparticles, CDN@VLP enhances DC‐specific uptake by 1.9‐fold while reducing non‐specific T cell internalization in tumors by 14.8‐fold, achieving comparable antitumor efficacy at one‐fortieth the dose of free CDN. Systematic screening identifies an optimal VLP subtype that improves targeted accumulation in type 1 conventional DCs (cDC1s)—a subset essential for STING pathway activation—by 2.3‐fold and amplifies durable type I interferon responses, resulting in a 12.8‐fold increase in IFN‐β production. Transcriptomic analysis further reveals that CDN@VLP promotes cDC1 recruitment into tumors by enhancing the secretion of key chemokines (XCL1, CCL4, and CCL5), suggesting an additional mechanism of action. By mimicking viral tropism, the CDN@VLP platform establishes a paradigm for precision STING activation, overcoming the trade‐off between potency and specificity in cDC1‐targeted immunotherapy.