Nanoparticle therapeutics in FSHD: current research and future perspectives

Abstract

Facioscapulohumeral muscular dystrophy (FSHD) is a hereditary neuromuscular disorder characterized by progressive, asymmetric muscle weakness caused by aberrant expression of the DUX4 (double homeobox 4) transcription factor. There are currently no disease-modifying treatments available, and treatment options remain restricted to supportive and symptomatic measures despite advances in understanding its molecular basis. Efforts have been made to develop therapeutic approaches targeting DUX4 silencing, genome editing, and downstream pathogenic pathway modification to address its unmet clinical need. Clinical translation is still hampered by the lack of effective, targeted delivery to skeletal muscle. Nanotechnology-based carriers are promising for overcoming these obstacles, as they improve tissue targeting while reducing off-target distribution and therapeutic payload. In this review, we address the current landscape of FSHD therapeutics and highlight how preclinical data on nanotherapeutics in Duchenne muscular dystrophy and other muscular dystrophies demonstrate the viability of nanoparticle-mediated strategies for muscle-targeted delivery and improved systemic bioavailability, making this an emerging approach in FSHD therapeutics. We also address issues with nanoparticle-based approaches for clinical use, including gaps in long-term safety, scalability, and efficiency. By integrating insights from the molecular genetics of FSHD and advances in nanomedicine in other muscular dystrophies, this review aims to provide a comprehensive perspective on the potential of nanotherapeutics and to outline future directions for their clinical translation in FSHD.