Supramolecular adenosine-based skin delivery system for hair regulation and restoration

Adenosine (Ado) is known for its well-established biological activities in regulating inflammation, oxidative stress, and tissue repair. However, its practical application is limited by poor water solubility, low transdermal permeability, and inadequate stability, which collectively hinder its bioavailability and target efficacy. In this study, a novel supramolecular cocrystal (TA–Ado) was constructed through hydrogen-bond–driven self-assembly of Adenosine with a small-molecule coformer, aiming to simultaneously improve its physicochemical properties and biological performance. Molecular modeling, quantum calculations, and spectroscopic analyses confirmed the structural stability and crystalline independence of TA–Ado, and the optimal molar ratio was determined. In vitro studies demonstrated that TA–Ado significantly enhanced the transdermal permeation of Adenosine by 2.66-fold while maintaining excellent biocompatibility. Moreover, TA–Ado exhibited superior synergistic bioactivity over free Adenosine and physical mixtures across multiple dimensions, including antioxidant, anti-inflammatory, antimicrobial, and sebum-regulating effects. Notably, TA–Ado inhibited 5α-reductase activity by up to 81.93%, promoted ex vivo hair follicle growth, and improved cuticle integrity. Clinical evaluations further confirmed its high safety, stability, and efficacy in alleviating scalp inflammation, reducing sebum secretion, and preventing hair loss. In summary, the TA–Ado cocrystal provides an efficient delivery platform for Adenosine, offering a promising strategy for the development of supramolecular functional materials in dermatological and cosmetic applications.