Ultrathin Oleanolic Acid/Perfluorocarbon-Ferrocene Nanosheets Trigger Reactive Species Storm to Reshape Tumor Microenvironment for Enhanced Chemodynamic Therapy

Ferrocene derivatives possess a typical "sandwich" structure that facilitates the formation of two-dimensional nanosheets (2D NSs), while their ferrous ions can effectively mediate chemodynamic therapy (CDT). However, conventional bottom-up synthesis methods for nanosheets often involve complex processes and stringent preparation conditions, limiting their therapeutic applications. In this study, we developed a simple yet efficient premix-dropwise-stir synthetic strategy to fabricate ultrathin oleanolic acid/perfluorocarbon-ferrocene (O/F-Fc) 2D NSs with considerable antitumor properties. The incorporation of oleanolic acid (OA) effectively inhibited F-Fc self-aggregation and facilitated the formation of ultrathin nanosheets (∼1.5 nm), while simultaneously enhancing the CDT efficacy of F-Fc through synergistic effects. Comprehensive in vitro and in vivo studies demonstrated that these carrier-free 2D NSs possess multifunctional capabilities, including oxygen self-supply to alleviate tumor hypoxia, generation of multiple reactive oxygen/nitrogen species to amplify oxidative stress and enhance CDT, antifibrotic activity, promotion of macrophage M1 polarization to activate immune responses, and enhanced deep tumor penetration, collectively enabling effective tumor microenvironment (TME) remodeling. This study not only presents an approach for preparing ultrathin ferrocene-based carrier-free 2D NSs, but also offers mechanistic insights into developing carrier-free organic 2D nanosystems for synergistic TME remodeling and enhanced CDT efficacy in cancer therapy.