Artemisinin-derived radicals trigger TGFβ oxidation and degradation for alopecia therapy

Protein oxidation orchestrates hair follicle anagen transition and regeneration by mediating the activation or degradation of target proteins. However, current oxidative strategies primarily rely on exogenous reactive oxygen species (ROS) supplementation, which is plagued by poor selectivity and severe off-target oxidative damage. Herein, we propose a targeted protein oxidation strategy for the treatment of androgenetic alopecia (AGA), and engineer artemisinin (ART)-based lipid nanoparticles (EPC/CS@ART NPs) via self-assembly of cholesterol (CS), egg phosphatidylcholine (EPC), and ART. These nanoparticles achieve efficient penetration into human dermal papilla cells (hDPCs) within the hair follicular regions. Upon internalization, ART responds to the intracellular metal ion microenvironment to generate ART-derived radicals, which potently promote hDPCs proliferation and ex vivo hair shaft elongation. Mechanistically, ART-derived radicals preferentially interact with TGFβ via spatial structural matching, and subsequently induce oxidative modification of TGFβ and its degradation predominantly through the ubiquitin-proteasome system (UPS), thereby blocking the Smad2/3 signaling pathway. In vivo AGA models further confirmed that EPC/CS@ART NPs exerted robust hair regeneration efficacy. This protein oxidation strategy not only presents a novel therapeutic approach for AGA treatment but also expands the therapeutic potential of artemisinin-based nanomedicine.