Non-invasive skin topical delivery of hyaluronan

Hyaluronic acid (HA), a key glycosaminoglycan in the skin extracellular matrix, diminishes with aging, leading to dryness, wrinkles, and loss of elasticity. While subcutaneous HA injection remains the standard treatment, it is invasive and associated with complications. Here, we developed a zwitterionic polymer-based nanogel system (HA/OP) for noninvasive transdermal HA delivery. The nanogels, formed by complexing HA with poly[2-(N-oxide-N,N-diethylamino)ethyl methacrylate] (OP), exhibited pH-responsive behavior, remaining stable at weakly acidic skin surface pH (∼5) but dissociating in neutral dermal environments. HA/OP nanogels efficiently permeated the stratum corneum via sebum-assisted enrichment and para-corneocyte transport, followed by transcytosis and enhanced paracellular penetration mediated by myosin light-chain kinase (MLCK) upregulation. This enabled deep HA deposition in the dermis and subcutaneous tissue, significantly improving skin hydration and reducing wrinkles in hairless mice without irritation. Our findings present a safe, needle-free strategy for topical HA delivery, addressing a major unmet need in cosmetic and dermatological applications.