Dual-State Tumor-Activated RNA Delivery for Tumor-Selective and Precision Therapy.

Abstract

RNA therapeutics hold transformative potential for precision oncology; however, their systemic application remains constrained by a fundamental tradeoff between prolonged circulation stability and efficient intracellular activation. 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.