The recent understanding of the pathogenic mechanisms of MDs highlights the urgent need of new and more effective treatments [20,100]. Nanomedicine demonstrated to enhance the therapeutic potential of gene therapy and drug repurposing approaches. As an example, pentamidine-loaded nanomedicines were used to explore the activity of the drug, not only as an anti-leishmaniasis agent but also as an anticancer agent to reduce drug associated toxicity, such as its severe nephrotoxicity [271,272]. Ongoing investigations are aimed at demonstrating the efficacy of this novel formulation to treat DM1 (study in progress).

New therapeutic approaches needed a continuous administration throughout patient’s life, making the biocompatibility and biodegradability of delivery systems a crucial feature to preserve skeletal muscle from additional alterations. As presented in this review, the main advantages of nanosystems rely on their physico-chemical properties, namely composition, size and surface potential that can be modulated to avoid nanocarrier toxicity, and to load specific actives and deliver them in a target site.

To disclose the potential of nanomedicine application to MDs treatment, the gap between in vitro and in vivo testing has to be filled. In addition, to understand the fate of nanosystems once administered to MDs mice, biodistribution studies need to be addressed. To date, only a few investigations reported NPs biodistribution into skeletal muscles through different administration routes as I.V., I.P. and I.M. (tibialis anterior and gastrocnemius muscles) [173,273,274]. After systemic administration, NPs spread into tissues through blood systemic circulation, then, extravasate into the ECM before reaching muscle fibres. It has been suggested that the dense blood capillary network wrapping skeletal myofibers could be favourable to NPs accumulation and distribution following I.V. injection [196]. Hydrodynamic injection is also known to facilitate gene delivery by transient enhancement of the plasma membrane’s permeability [142,275,276]. However, the applied pressure due to the hindrance of the blood flow might cause oedema and inflammation, restricting the translation of this technique to clinic [277].

Overcoming the ECM barrier remains another important goal to improve NPs distribution in skeletal muscle fibres. Surface engineered nanosystems have been designed to actively promote the interaction between nanosystems and cells [278]. The high specificity of antibodies for their corresponding antigen provides a selective and potent approach for therapeutic NPs targeting [279]. As an example, the murine monoclonal antibody (3E10), capable of binding the surface of muscle cells, has been reported to improve active targeting [280,281]. However, no scientific studies on antibody-functionalised NPs have been conducted for skeletal muscle targeting so far. More commonly used, short peptides sequences (e.g., ASSLNIA or SKTFNTHPQSTP) have proved promising as NPs functionalization for specific tissue-targeting [282,283,284]. Several examples of peptides targeting muscle cells have been reported [285,286,287] and association to nanosystems may lead to improved selectivity of NPs for skeletal muscle. Polymeric nanosystems have been functionalised with active targeting agents that preferentially bind active molecules or receptors expressed on the surface of muscle cells. Active targeting-dependent uptake has been demonstrated using PLGA nanocarriers functionalised with a muscle-homing peptide M12 [288]. Biodistribution studies revealed a preferential accumulation of targeted NPs in skeletal muscle cells in mdx mice, compared to untargeted nanocarriers, increasing the accumulation of polymeric NPs and enhancing therapeutic efficacy [274].