A biocompatible tea polyphenol nanoplatform for efficient cytosolic delivery of protein therapeutics

Intracellular protein therapeutics offer great promise for treating diseases involving intracellular targets, yet their clinical translation remains limited by inefficient delivery systems. Here, we report the development of a simple, versatile, and biocompatible protein delivery platform based on tea polyphenol nanoparticles (TPNs) formed via the oxidative self-polymerization of epigallocatechin gallate (EGCG). Through noncovalent interactions between EGCG and proteins, TPNs enable efficient encapsulation of proteins with diverse molecular weights and isoelectric points under mild conditions. Using urate oxidase (UOx) as a model therapeutic protein, we demonstrate that TPNs protect UOx from enzymatic degradation, preserve its native structure and enzymatic activity, and achieve effective cytosolic delivery via glutathione-triggered release. In disease models of hyperuricemia and gouty arthritis, TPNs/UOx significantly prolonged UOx circulation, lowered serum uric acid levels, reduced joint inflammation, and improved liver and kidney function, with favorable biocompatibility. This work establishes TPNs as a versatile and stimuli-responsive platform for intracellular protein delivery, offering new strategies for the clinical application of protein therapeutics.