Copper Metal–Organic Framework‐Embedded Decellularized Matrix Hydrogel Remodels the Uterine Microenvironment for Endometrial Regeneration and Fertility Restoration

ABSTRACT Severe endometrial injury is a leading cause of female infertility, driven by the convergence of inadequate vascularization, persistent inflammation, infection, and excessive fibrosis. Existing therapies address these pathologies in isolation, falling short of the coordinated remodeling essential for functional regeneration. Here, we report an injectable, thermally responsive composite hydrogel that embeds copper‐based metal–organic framework (HKUST‐1) nanoparticles within a porcine acellular dermal matrix (PADM) network, coupling biomimetic extracellular matrix support with sustained Cu 2 + delivery. In vitro, the hydrogel promotes endothelial migration and tubular network formation, shifts macrophage polarization toward the reparative M2 phenotype, and exhibits broad‐spectrum bactericidal activity. In a rat endometrial injury model, it increases gland density and CD31 + neovascularization while suppressing fibrotic collagen deposition. Crucially, it restores hormonal responsiveness by upregulating estrogen and progesterone receptor expression. These coordinated improvements translate into meaningful fertility restoration, with implanted embryos increasing from 8 ± 2 to 14 ± 1. Transcriptomic profiling indicates coordinated changes in extracellular matrix remodeling and ion transport programs. The PADM@HKUST‐1 hydrogel demonstrates that integrating biomimetic scaffolding with sustained bioactive ion delivery achieves comprehensive uterine microenvironment remodeling, offering a translatable approach for clinical management of severe endometrial injury.