Abstract
Despite considerable advances in cancer therapy, the intrinsic heterogeneity of malignant cells continues to compromise therapeutic efficacy with conventional monotherapies, driving the need for combination treatments to achieve more durable and complete responses. The limited efficacy of conventional chemotherapy is largely attributable to the immunosuppressive tumor microenvironment, which is frequently perpetuated by epigenetic mechanisms, including aberrant DNA methylation. To overcome these limitations, we hypothesized that Decitabine (Dac)-mediated sensitization could dramatically enhance Sorafenib (Sor)-induced ferroptosis, and to test this synergy, we developed an innovative biomimetic codelivery platform comprising polymer micelles loaded with Sor surface-coated with exosomes encapsulating Dac (Exo&PM/D + S). This platform facilitates codelivery, enabling Dac-mediated DNA hypomethylation to remodel the tumor microenvironment and promote Sor-triggered ferroptosis. In vitro, Exo&PM/D + S exhibited potent anti-tumor activity by concurrently enhancing DNA demethylation and ROS accumulation. In mouse neuroblastoma models, the system significantly suppressed tumor growth, stimulated antitumor immunity, and extended survival. Mechanistic studies confirmed that Dac potentiates Sor-induced ferroptosis through epigenetic modulation. Thus, Exo&PM/D + S represents a promising nanotherapeutic strategy that synergizes epigenetic modulation with ferroptosis induction for enhanced anti-tumor efficacy.