Protein Transduction System Based on Tryptophan-zipper against Intracellular Infections via Inhibiting Ferroptosis of Macrophages

Cells penetrating molecules in living systems hold promise of capturing and eliminating threats and damage that can plan intracellular fate promptly. However, it remains challenging to construct cell penetration systems that are physiologically stable with predictable self-assembly behavior and well-defined mechanisms. In this study, we develop a core–shell nanoparticle using a hyaluronic acid (HA)-coated protein transduction domain (PTD) derived from the human immunodeficiency virus (HIV). This nanoparticle can encapsulate pathogens, transporting the PTD into macrophages via lipid rafts. PTD forms hydrogen bonds with the components of the membrane through TAT, which has a high density of positive charges and reduces the degree of membrane order through Tryptophan (Trp)-zipper binding to the acyl tails of phospholipid molecules. HA-encapsulated PTD increases the resistance to trypsin and proteinase K, thereby penetrating macrophages and eliminating intracellular infections. Interestingly, the nonagglutination mechanism of PTD against pathogens ensures the safe operation of the cellular system. Importantly, PTD can activate the critical pathway of antiferroptosis in macrophages against pathogen infection. The nanoparticles developed in this study demonstrate safety and efficacy against Gram-negative and Gram-positive pathogens in three animal models. Overall, this work highlights the effectiveness of the PTD nanoparticle in encapsulating pathogens and provides a paradigm for transduction systems-anti-intracellular infection therapy.