Reduction of Ultraviolet‐ and Heat‐Induced Aging Using Betulin‐Loaded Arginine–Caprylate Self‐Assembly: Randomized Double‐Blind Clinical Trials

Background Betulin exhibits potent antibacterial, anti‐inflammatory, and antioxidant properties, effectively preventing ultraviolet (UV)‐ and heat‐induced skin aging. Its limited solubility in cosmetic solvents restricts its application. Methods To enhance betulin's applicability, a self‐assembled nanocarrier, arginine–caprylate ion pair loaded with betulin (B‐ACS), was developed. Structural properties, loading efficiency, skin permeability, and antioxidant activity were assessed. UVB‐induced damage was examined in human keratinocytes (HaCaT; n = 3) by measuring inflammatory cytokines and matrix metalloproteinases (MMPs) via ELISA. Three‐dimensional reconstructed human skin models were exposed to UVA (10 J/cm 2 ) to evaluate collagen and aquaporin‐3 protection. A pilot randomized, double‐blind, placebo‐controlled clinical trial ( n = 12, 2 weeks) assessed 3 % (w/w) B‐ACS cream on UV‐ and infrared‐induced skin damage. Results B‐ACS showed a particle size of 236.9 ± 10.3 nm, 98.3 ± 1.3 % encapsulation efficacy, and superior reactive oxygen species (ROS) scavenging (IC50 = 4.87 ppm) compared to free betulin (IC50 = 8.26 ppm). In HaCaT cells, B‐ACS significantly reduced UVB‐induced inflammatory cytokine and MMP expressions ( p < 0.05). In reconstructed skin, it prevented UVA‐induced collagen and aquaporin‐3 degradation. Clinically, 3% B‐ACS cream significantly improved elasticity (1.69‐fold), brightness (2.59‐fold), and pigmentation (1.91‐fold); transepidermal water loss (TEWL) and heat‐aging markers decreased 1.39‐fold and 1.63‐fold versus placebo, respectively ( p < 0.05). Conclusion B‐ACS enhances betulin's solubility and delivery, offering potent efficacy against UV‐ and heat‐induced aging.