A hyaluronic acid-based microneedle platform for enhanced ferroptosis-induced tumor therapy and antibacterial applications

Skin cancer, particularly malignant melanoma, remains a highly aggressive and treatment-resistant malignancy. Although current therapeutic approaches, including surgical excision, have been employed, they often face limitations in terms of efficacy and the occurrence of secondary bacterial infections. Ferroptosis, an iron-dependent cell death mechanism triggered by lipid peroxidation, has shown potential for melanoma treatment; however, melanomas exhibit intrinsic resistance to ferroptosis. In this study, we developed a hyaluronic acid (HA)-based microneedle (FeSSZ/MN) platform encapsulated with iron carbonate (FeCO 3 -PEG) and sulfasalazine (SSZ) to enhance ferroptosis induction and overcome melanoma resistance. FeCO 3 -PEG triggers Fenton reactions in vivo , generating reactive oxygen species (ROS) that deplete glutathione (GSH), inhibit glutathione peroxidase 4 (GPX4), and amplify lipid peroxidation, thereby inducing ferroptosis in tumor cells. SSZ further potentiates this effect by inhibiting the cystine/glutamate antiporter xCT, leading to additional GSH and thiol depletion and further enhancement of ferroptosis. Moreover, this platform exhibits antibacterial activity, as iron overload in bacteria induces ferroptosis-like cell death, effectively eradicating pathogens. The FeSSZ/MN platform thus offers a multifunctional, targeted approach for treating melanoma and controlling bacterial infections, providing a promising strategy to overcome tumor resistance and infection-related complications.