Nanoenabled Hyaluronic Acid-Based Topical Delivery of Kaempferol and Ferulic Acid: Chemomodulatory Potential Against DMBA-Croton Oil-Induced Skin Carcinogenesis in Male Swiss Albino Mice

Background/Objectives: Skin cancer is a major health concern worldwide and has led to the quest for safer and more effective topical chemopreventive agents. In this study, the in vivo efficacy of a hydrogel formulation containing kaempferol and ferulic acid-loaded nanoparticles was evaluated for the management of DMBA-croton oil-induced skin cancer in Swiss albino mice. Methods: Drug-loaded nanoparticles prepared via nanoprecipitation were incorporated into hyaluronic acid to obtain single-drug (FAPG, KMPG) and dual-drug-loaded (FKMG) hydrogel formulations. Skin tumors were induced via DMBA as an initiator followed by croton oil as a promoter, with tumor onset observed after a similar latency period of approximately 5–6 weeks in all carcinogen-exposed groups. Treatment was initiated after week 6 and continued until week 16. Results: The gel formulation had a skin-compatible pH and the desired rheological and spreadability properties. The dual drug-loaded hydrogel formulation had a more controlled and prolonged release profile. Compared with the negative and vehicle control groups, the FKMG-treated group presented a marked reduction in tumor incidence and tumor burden, along with improved body weight gain. Biochemical analysis revealed the restoration of antioxidant and enzyme activity in treated animals, particularly in animals treated with FKMG. Histopathological examination revealed near-normal skin architecture in FKMG-treated mice, indicating strong protective effects. Additionally, significant downregulation of TNF-α and IL-6 suggested effective suppression of tumor-promoting inflammatory pathways. Conclusions: Overall, the FKMG formulation exhibited superior chemopreventive efficacy compared with the FAPG and KMPG treatments, highlighting its potential as a promising topical therapeutic strategy against chemically induced skin carcinogenesis.