Nanoparticle‐Modified Nanofibers Induce Ferroptosis and Stimulate Antitumor Immunity for Melanoma Therapy

Melanoma, a highly aggressive and therapy-resistant cutaneous malignancy, presents formidable clinical challenges owing to its propensity for early metastasis and frequent postoperative recurrence. Here, a nanofiber-based drug delivery system (5F/STFM/R-ES) is developed that synergistically induces ferroptosis and potentiates immunotherapy to inhibit melanoma growth and reduce the risk of metastasis and recurrence. To this end, mesoporous silica nanoparticles encapsulating resiquimod (R848) are surface-coated with Fe/Mn-based metal-polyphenol networks (TFM) to form STFM/R. Subsequently, STFM/R is electrospun into 5-fluorouracil-loaded nanofibers. When applied to the tumor site, 5-fluorouracil and STFM/R are released. Following the degradation of STFM/R, the release of Fe²⁺ triggered ferroptosis through iron overload, while the simultaneous liberation of Mn²⁺ synergizes with R848 to activate the cGAS-STING signaling pathway. This multifunctional strategy promotes the maturation of dendritic cells and repolarizes tumor-associated macrophages from M2 to M1. The in vivo and in vitro evaluations reveal that 5F/STFM/R-ES significantly improves delivery efficacy, remodels the immunosuppressive tumor microenvironment, and enhances the therapeutic efficacy of chemotherapeutics. The localized delivery strategy of the platform minimizes systemic toxicity while achieving combinatorial therapeutic effects, highlighting its potential for personalized melanoma therapy.