Advancing Skin Rejuvenation Through Ultrasound-Enhanced Non-Invasive Delivery of Hyaluronic Acid Nanoparticles

High-molecular-weight hyaluronic acid (HMw-HA) is widely used for skin rejuvenation and anti-aging. However, its rapid degradation and <24 h cutaneous residence limit its therapeutic potential. Cross-linked HA fillers were developed to improve longevity, but their high viscosity and invasive administration may reduce biocompatibility and patient comfort. To overcome these challenges, we developed a biocompatible nanocarrier based on quaternized starch (Q-starch) that encapsulates linear HMw-HA into nanoparticles (NPs) of ~100 nm with a ζ-potential of ~-35 mV. These NPs retained spherical morphology over seven days without aggregation. The resulting HMw-HA-NPs significantly improved HA stability and extended its skin residence time compared to commercially available HA, while preserving its biological function to stimulate collagen production in murine models. To enable non-invasive delivery, we applied low-frequency ultrasound (LFUS), which transiently enhanced skin permeability, facilitated deeper NPs penetration, and further elevated collagen at day 14. Altogether, this strategy offers a promising needle-free alternative to traditional HA treatments by improving stability, skin penetration, and therapeutic efficacy. The combination of HMw-HA-NPs with LFUS addresses key limitations of current dermo-esthetic therapies and supports the development of patient-friendly skin rejuvenation technologies.