Targeting Drug Delivery System to Skeletal Muscles: A Comprehensive Review of Different Approaches

The skeletal muscle is one of the largest organs in the body and is responsible for the mechanical activity required for posture, movement and breathing. The effects of current pharmaceutical therapies for skeletal muscle diseases are far from satisfactory; approximately 24% of Duchenne muscular dystrophy (DMD) trials have been terminated because of unsatisfactory outcomes. The lack of a skeletal muscle-targeting strategy is a major reason for these unsuccessful trials, contributing to low efficiency and severe side effects. The development of targeting strategies for skeletal muscle-specific drug delivery has shown the potential for increasing drug concentrations in the skeletal muscle, minimising off-target effects, and thereby improving the therapeutic effects of drugs. Over the past few decades, novel methods for specifically delivering cargo to skeletal muscles have been developed. In this review, we categorise targeting methods into four types: peptides, antibodies, small molecules and aptamers. Most research has focused on peptide and antibody ligands, and there are several well-established drugs in this category; however, drawbacks such as protease degradation and immunogenicity limit their use. Aptamers and small molecules have low immunogenicity and are simple to chemically produce. However, small molecule ligands generally exhibit lower affinity because of their small size and high mobility. Aptamers are promising ligands for skeletal muscle-targeting delivery systems. Additionally, if the active site of the cargo is located inside the cell, an internalisation pathway becomes necessary. The order of internalisation ligands and targeting ligands in the complex is a crucial factor, because an inappropriate order could lead to much lower targeting and internalisation efficiencies. Moreover, ligand density also merits consideration, as increasing the density of the targeting ligands may result in steric hindrance, which could impact the accessibility of the receptor and cause enlargement of the targeted ligands. More efforts are required to optimise drug delivery systems that specifically recognise skeletal muscle, with the aim of enhancing quality of life and promoting patient well-being.