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Gene therapy that employs therapeutic nucleic acids to modulate gene expression has shown great promise for diseases therapy, and its clinical application relies on the development of effective gene vector. Herein a novel gene delivery strategy by just using natural polyphenol (‐)‐epigallocatechin‐3‐O‐gallate (EGCG) as raw material is reported. EGCG first intercalates into nucleic acids to yield a complex, which then oxidizes and self‐polymerizes to form tea polyphenols nanoparticles (TPNs) for effective nucleic acids encapsulation. This is a general method to load any types of nucleic acids with single or double strands and short or long sequences. Such TPNs‐based vector achieves comparable gene loading capacity to commonly used cationic materials, but showing lower cytotoxicity. TPNs can effectively penetrate inside cells, escape from endo/lysosomes, and release nucleic acids in response to intracellular glutathione to exert biological functions. To demonstrate the in vivo application, an anti‐caspase‐3 small interfering ribonucleic acid is loaded into TPNs to treat concanavalin A‐induced acute hepatitis, and excellent therapeutic efficacy is obtained in combination with the intrinsic activities of TPNs vector. This work provides a simple, versatile, and cost‐effective gene delivery strategy. Given the biocompatibility and intrinsic biofunctions, this TPNs‐based gene vector holds great potential to treat various diseases. [ABSTRACT FROM AUTHOR]