Transcytotic transportation of size-controlled nanocarriers into dystrophic skeletal muscle leads to therapeutic outcome in mice.

Abstract

Duchenne Muscular Dystrophy (DMD) is a lethal muscle-wasting disorder with limited therapeutic options. Although nano drug delivery offers promise, the biodistribution and access routes to dystrophic muscle remain poorly understood. Here we show that intravenously administered mesoporous silica nanoparticle (MSNP) carriers exhibit striking size-dependent biodistribution in male DMD mice. Small nanocarriers (50~100 nm) efficiently accumulate in skeletal muscle while avoiding hepatic and splenic sequestration, outperforming larger particles (200~300 nm). Importantly, we uncover that endothelial transcytosis, not passive vascular leakage, is the dominant and previously unrecognized route by which nanocarriers access dystrophic muscles. Further, we encapsulate tamoxifen, a repurposed drug, into optimized MSNPs. This intervention increases utrophin expression, reduces fibrosis, and diminishes myofiber necrosis, resulting in improved muscle health and strength. Our results establish size-tuned, transcytosis-enabled nanocarriers as a transformative strategy for targeted drug delivery to dystrophic muscle, paving the way for nanomedicine-based therapies in DMD and potentially other muscle disorders.