Homologous Tremella fuciformis semi-IPN hydrogels with entanglement-assisted network stabilization for near-neutral pH-responsive photodamage therapy.

Healthy skin maintains a weakly acidic surface pH (4.1-5.8), whereas barrier disruption and acute inflammation may shift the local microenvironment toward near-neutral conditions. However, most stimuli-responsive hydrogels are designed for acidic environments, limiting their suitability for photodamaged skin. To address this, we developed a homologous semi-interpenetrating polymer network (semi-IPN) hydrogel by integrating native Tremella fuciformis polysaccharides (TFPs), oxidized TFPs (OTFPs), and carboxymethyl chitosan (CMCS) for near-neutral pH-responsive transdermal delivery of quercetin (QT). Native TFPs introduced long-chain physical chain entanglement, improving network stability, flexibility (96.6% strain), and water retention. 10 wt% CMCS increased the apparent solubility of QT to 2409.8 μg/mL and facilitated homogeneous drug dispersion. Benefiting from the high hydration capacity of TFPs, the system enhanced transdermal delivery, achieving a 6.2-fold increase in permeability compared with glyoxal (GA)-crosslinked hydrogels. The semi-IPN hydrogel showed near-neutral pH-responsive swelling behavior, increasing from 2829% at pH 4.5 to 4275% at pH 7.4, which triggered 59.7% QT release within 24 h. In vitro, the hydrogel restored HaCaT cell viability to 90.5% and reduced reactive oxygen species (ROS) by 76.9% after UVB exposure. In vivo, it accelerated structural repair, reducing epidermal thickness from 202.5 μm to 54.6 μm and increasing collagen content to 41.4%, while also providing photoprotection. This work presents a near-neutral pH-responsive homologous polysaccharide hydrogel for transdermal photodamage therapy and protection.