Highly uniform Cu/Fe-LDH synthesized by a UNISON method for MRI-guided ferroptosis/cuproptosis therapy and immune microenvironment remodeling of tumors

초록

The clinical translation of layered double hydroxides (LDH) is impeded by the challenge of synthesizing populations with high physicochemical uniformity, which dictates their in vivo pharmacokinetics and therapeutic reproducibility. Conventional synthesis methods yield polydisperse products due to the spatiotemporal overlap of nucleation and growth, and reported improvements failed to fundamentally resolve the heterogeneity of initial nuclei. Herein, we report a novel LDH synthesis method named as uniform nuclei via isolation & synchronized Ostwald nanosynthesis (UNISON). The UNISON method introduces a critical room-temperature aging step, which utilizes mild Ostwald ripening to thermodynamically screen and eliminate defective nuclei, and preserve high-quality seeds for subsequent hydrothermal growth, yielding LDH with exceptional monodispersity and crystallinity. Leveraging the highly uniform Cu/Fe-LDH for magnetic resonance imaging (MRI) guided synergistic ferroptosis/cuproptosis therapy of tumors, lonidamine (LND) was loaded in the interlayer of Cu/Fe-LDH followed by surface modification with a macrochelate of polyacrylic acid and gadolinium (Gd-PAA), generating Cu/Fe-LDH@LND@Gd-PAA. Cu/Fe-LDH@LND@Gd-PAA synergizes LND-mediated metabolic regulation with LDH-induced acid neutralization to remodel the immunosuppressive tumor microenvironment. The released Cu2+ and Fe3+ triggers cuproptosis and ferroptosis, amplifying antitumor efficacy. The in vitro and in vivo data demonstrate the UNISON is a promising method for synthesis of 2D nanomedicines with clinical potential. © 2026 Elsevier B.V.

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