Dynamic Covalent Dual Prodrug Assemblies for Endometritis Therapy via Inflammation Alleviation, Tissue Repair, and Reproductive Function Restoration.

Abstract

Endometritis is an inflammatory disorder of the endometrium triggered by microbial infection or immune dysregulation, and current therapies, which are largely single-targeted, fail to coordinate multiple mechanisms. Here, we report a dynamic covalent dual prodrug nanoplatform (termed SFB) that integrates the anti-inflammatory, antiapoptotic, and proautophagic effects of spermidine (SPD) and baicalein (BAI). Using phenylboronic acid-mediated linkage and reaction-induced self-assembly (RISA), SFB formed well-defined nanostructures with an exceptionally high dual-drug encapsulation (exceeding 90%). These assemblies enabled responsive and synchronized release under acidic and oxidative inflammatory microenvironments while exhibiting favorable stability and biosafety. Mechanistic studies revealed that SFB efficiently scavenged reactive oxygen species, suppressed TLR/MyD88/NF-κB-mediated inflammation, inhibited apoptosis, and restored autophagy-lysosomal homeostasis. In a mouse model of endometritis, SFB treatment markedly reduced oxidative stress, promoted tissue repair, improved endometrial receptivity, and rescued reproductive impairments associated with embryo implantation and fetal development. Collectively, SFB represents a multifunctional dynamic covalent nanoplatform that enhances therapeutic efficacy against endometrial inflammation, improves reproductive outcomes, and overcomes key limitations of conventional dual-drug delivery strategies, offering opportunities for multidrug synergistic therapy.