Light‐Activatable Hyaluronic Acid‐Derivatives Releasing Nitric Oxide and Their Delivery in the Skin

Hyaluronic acid (HA), renowned for its hydrating properties, penetrates deeper into the skin at a very low molecular weight, promoting cellular repair and reducing inflammation. Nitric oxide (NO), a gaseous mediator with a very relevant role in many physiological and pathophysiological processes, is expected to complement the functions of HA in the skin through its vasodilatory, anti-inflammatory, and regenerative properties. Herein, a novel class of HA derivatives functionalized with NO photodonors (NOPD) for light-activated therapeutic applications is introduced. The HA derivatives HA-NOPD1 and HA-NOPD2 demonstrated NO release under blue light activation. Biological assays on HaCaT keratinocytes revealed enhanced proliferation and migration under light stimuli, underscoring the therapeutic potential of HA-NOPD1. The derivatives are formulated into microemulsions (MEs) to allow their skin transport. MEs loaded with the photoresponsive derivatives are stable in the dark and provide effective NO photorelease with higher quantum yields than the free compounds. Skin permeation studies using porcine and artificial membranes confirmed that HA-NOPD2 distributed in all the skin layers, reaching the dermis and releasing NO in situ.