Pulmonary arterial hypertension remains one of cardiopulmonary medicine's most intractable conditions — current approved therapies manage symptoms without reversing underlying vascular remodeling. The growing recognition that microRNA dysregulation sits at the mechanistic core of PAH progression has energized a new class of therapeutic candidates, but translating RNA-based interventions from bench to bedside has long been constrained by the fragility of these molecules in biological environments.
This review in Current Medicinal Chemistry systematically maps the landscape of miRNA delivery strategies for PAH across four modalities: chemically modified nucleoside analogues that resist enzymatic degradation, viral vectors (primarily adeno-associated virus constructs), non-viral platforms including lipid nanoparticles and polymeric carriers, and hybrid systems combining elements of both. The central finding is that hybrid delivery architectures — which pair the transfection efficiency of viral components with the immunological tolerability of synthetic carriers — outperform single-modality approaches in preclinical PAH models by simultaneously achieving sufficient miRNA payload delivery and more acceptable safety profiles. The analysis highlights specific miRNA pathways, including miR-21, miR-17/92 cluster, and miR-204, as recurring targets across these delivery experiments.
Situating this work within the broader therapeutic RNA field reveals both promise and persistent friction. Lipid nanoparticle technology, validated dramatically by mRNA COVID-19 vaccines, has accelerated non-viral RNA delivery, lending credibility to the overall approach. However, PAH presents an unusually demanding target: the pulmonary vasculature requires tissue-specific delivery to avoid off-target systemic effects, and long-term vascular remodeling demands sustained miRNA modulation rather than transient expression. This review is preclinical and largely synthesizes animal-model data, which historically overestimates translation success in PAH specifically — a field littered with therapies that reversed hypertension in rodents but failed in human trials. The hybrid systems are intellectually compelling, but they introduce compounded regulatory complexity. This is confirmatory-to-incremental work that responsibly frames boundaries; genuine clinical relevance awaits first-in-human data.