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Conventional polyethylene glycol (PEG)-based carriers provide antifouling protection but lack tumor responsiveness, resulting in limited tumor accumulation and suboptimal gene expression. In this study, we developed a nanosystem, the dual-state tumor-activated RNA platform (D-STAR), which enables a dynamic transition from a stealth circulatory state to an activated transfection state through stepwise environmental alternation by recognizing a narrow pH window. At physiological pH, D-STAR maintains a negative surface potential to minimize nonspecific interactions and extend its blood circulation. Within the tumor microenvironment and endo-\/lysosomal compartments, progressive protonation induces charge reversal and strengthens cationic activation, thereby enhancing tumor retention, cellular uptake, and cytoplasmic mRNA release. The systemic administration of D-STAR enabled tumor-selective mRNA expression with limited off-target organ distribution and markedly enhanced intratumoral reporter activity compared with PEG-based controls. The therapeutic delivery of human neutrophil elastase mRNA suppressed tumor growth and prolonged survival in a CT26 syngeneic model without systemic toxicity. Collectively, D-STAR establishes a dual-state adaptive RNA delivery framework that decouples systemic stability from activation potency, thereby offering a generalizable strategy for context-responsive precision RNA therapeutics.<\/jats:p>","DOI":"10.1021\/acsami.6c16995","type":"journal-article","created":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T19:01:47Z","timestamp":1792609307000},"source":"Crossref","is-referenced-by-count":0,"title":["Dual-State Tumor-Activated RNA Delivery for Tumor-Selective and Precision Therapy"],"prefix":"10.1021","author":[{"given":"Yuanshuai","family":"Song","sequence":"first","affiliation":[{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-cho, Midori-ku , , ,","place":["Yokohama, Kanagawa, Japan, 226-8501"]},{"name":"Institute of Science Tokyo , , 4259 Nagatsuta-cho, Midori-ku , , ,","place":["Yokohama, Kanagawa, Japan, 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