Time- and spatially resolved LNA delivery via thermally controlled SPION technology

Targeted RNA delivery with precise spatial and temporal control marks a significant advancement in therapeutic development, offering the potential to reduce drug dosages while minimizing off-target effects. In this study, we present a novel platform that employs superparamagnetic iron oxide nanoparticles (SPIONs) for externally controlled, thermally triggered, organ-specific locked nucleic acid (LNA) release. Our platform technology leverages a newly designed thermosensitive conjugate, based on a thermosensitive linker system that utilizes the thermal sensitivity of the tert-butyloxycarbonyl (Boc) group. This tool ensures stability during systemic circulation while enabling traceless, on-demand drug release at the target site. As a proof of concept, we applied this technology in a disease model of cardiac fibrosis, conjugating SPIONs with an inhibitor of microRNA (miRNA)-21, a key pro-fibrotic regulator. The nanoparticle system was thoroughly characterized for its stability, biocompatibility, and heat-induced release properties in vitro and subsequently validated for biodistribution, toxicology, and therapeutic potential in preclinical in vivo models. This innovative SPION-based delivery platform provides a versatile and precise framework for RNA-based therapeutics, with broad translational potential across various disease applications.