Multi-tissue miRNA networks in preterm birth: from molecular mechanisms to precision medicine.

Preterm birth (PTB) remains the leading cause of neonatal mortality and long-term complications worldwide, yet its molecular pathogenesis-particularly the coordinated regulation across different gestational tissues-is poorly understood. MicroRNAs (miRNAs) are key regulators of gene expression and exhibit tissue-specific patterns in pregnancy-related tissues, including the cervix, placenta, and amniotic membrane. This narrative review provides a comprehensive and integrative overview from a perspective of putative cross-tissue miRNA crosstalk. We summarize the differential miRNA expression profiles across gestational tissues and their associations with PTB, the tissue-specific mechanisms by which miRNAs regulate inflammatory responses, extracellular matrix remodeling, apoptosis, and barrier disruption, as well as the synergistic effects of multi-tissue-derived miRNAs and their potential as predictive biomarkers. We also evaluate the current status of miRNA-based therapeutic strategies. Our overview reveals that miRNA mimics (e.g., miR-21-5p, miR-199a-3p) and antagonists hold preclinical therapeutic potential in modulating inflammatory cascades and preserving cervical barrier function. However, clinical translation faces three major bottlenecks: the lack of pregnancy-specific delivery systems, safety concerns arising from the multi-target nature of miRNAs, and the challenge of targeting multi-tissue synergistic pathological changes with single-agent interventions. Emerging strategies-including exosome-based delivery, ligand-modified nanocarriers, and combination therapies-are currently being explored. The multi-tissue miRNA framework proposed in this review integrates miRNA biomarkers for early risk stratification with targeted therapeutic interventions, providing a new theoretical foundation for research directions in personalized risk assessment and targeted intervention strategies for PTB.