Transethosome‐Based Topical Administration Systems with Enhanced Penetration and Dual Actions for Treating EGFR‐Overexpressed Cutaneous Squamous Cell Carcinoma

Abstract Epidermal growth factor receptor (EGFR)‐overexpressing cutaneous squamous cell carcinoma (CSCC) necessitates more effective therapies due to its elevated metastasis risk compared to the conventional CSCC. While photodynamic therapy (PDT) is a promising way to treat CSCC, effectively administering photosensitizers to reach deeper skin malignancies remains a challenge. Herein, BE‐TEL is reported, a transethosome formulation designed to enhance skin and cutaneous tumor permeability, for targeted treatment of EGFR‐overexpressed CSCC. The formulation is co‐loaded with Erlotinib (Erb), a hydrophobic EGFR inhibitor, and BODIPY (BPY), a photosensitizer. Upon skin penetration and subsequent exposure to 660 nm light, BE‐TEL induces tumor cell apoptosis by reactive oxygen species (ROS) generation and EGFR pathway inhibition. ROS and Erb‐induced metabolic oxidative stress by upregulating the expression of NADPH oxidase 4 (NOX4) can enhance immunogenic cell death (ICD) and promote dendritic cell maturation for tumor‐specific immune response. Furthermore, the EGFR downregulation further mitigated the risk of metastasis and recurrence. In conclusion, BE‐TEL's superior penetration ability together with its combined PDT and EGFR targeted approach paves the way for an efficient strategy against EGFR‐overexpressed CSCC.