A liposome-in-hydrogel hybrid system for spatially targeted delivery and prolonged intradermal retention of vitamin K1 against EGFR inhibitor-induced skin toxicity.

Epidermal growth factor receptor (EGFR) inhibitors frequently cause cutaneous toxicities that impair patients' quality of life and may compromise treatment adherence. Although topical vitamin K1 (VK1) has shown therapeutic potential, its clinical efficacy remains inconsistent, largely due to poor distribution within pharmacologically relevant skin compartments, particularly the viable epidermis and pilosebaceous units. To address this, we developed a VK1-loaded liposome‑in‑hydrogel (VK1-Lipo-Gel) capable of sustaining intradermal drug residence while minimizing systemic exposure. Compared with the commercial VK1 cream, VK1-Lipo-Gel markedly prolonged VK1 retention in the skin. VK1 remained detectable in the viable epidermis-dermis (VED) for up to 36 h, yielding a Cmax of 1.64 ± 0.10 μg/cm2 at 8 h and an AUC0-36h of 33.16 ± 1.70 μg·h/cm2. Notably, the formulation promoted preferential localization within the VED and pilosebaceous units, with plasma VK1 levels below the LLOQ. More importantly, VK1‑Lipo‑Gel did not compromise the antitumor efficacy of erlotinib. In an erlotinib-induced skin toxicity model, by restoring EGFR-ERK signaling, VK1-Lipo-Gel more effectively reinforced epidermal barrier function, attenuated inflammatory responses, and ameliorated follicle‑associated alterations. These results demonstrate that optimizing intradermal retention and compartment‑specific distribution, rather than simply increasing transdermal flux, is a superior strategy for managing EGFR inhibitor-induced cutaneous toxicity, and support the translational potential of liposome‑hydrogel hybrids for topical drug delivery.