Abstract

Ultraviolet B (UVB) radiation is a major environmental factor that induces skin photodamage through oxidative stress and inflammation. To address this, we developed a reactive oxygen species (ROS)-responsive hydrogel, SeNPs@HPTA, for the intelligent delivery of biogenic selenium nanoparticles (BioSeNPs) synthesized by Bifidobacterium animalis. The hydrogel was fabricated by cross-linking phenylboronic acid-grafted hyaluronic acid (HA-PBA) with tannic acid (TA), forming dynamic boronic ester bonds that cleave under high ROS conditions to enable on-demand BioSeNPs release. Transcriptomic analysis revealed that B. lactis H15 efficiently reduces selenite (Se(IV)) to elemental SeNPs by upregulating ion transport and NADPH-regenerating pathways. In vitro, SeNPs@HPTA enhanced HaCaT cell viability, scavenged ROS, and promoted cell migration post-UVB irradiation. In vivo, topical application alleviated skin lesions, improved hydration, reduced epidermal hyperplasia, and suppressed collagen degradation. Mechanistically, the hydrogel conferred therapeutic effects by enhancing antioxidant defenses, inhibiting inflammation and attenuating ferroptosis via GPx4/Nrf2 activation. Critically, genetic knockdown of GPx4 abolished its therapeutic effects, establishing a strict dependence on this key selenoenzyme. The formulation exhibited an excellent biosafety profile. This study presents a microbiome-inspired, stimulus-responsive strategy for precise skin photodamage treatment. We anticipate this microbiome-inspired, intelligent delivery system will offer a powerful and precise strategy for treating oxidative stress-related dermatoses.