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Growing evidence implicates mitochondrial dysfunction, oxidative stress, and impaired muscle energy homeostasis as central drivers of statin-induced muscle injury, with important consequences for patient adherence and treatment durability. Emerging nanocarrier-based drug delivery strategies provide an opportunity to address these limitations by reprogramming statin biodistribution, intracellular exposure, and release kinetics in a biologically informed manner. This review critically examines preclinical and early clinical studies of nanoformulated statins, including solid lipid nanoparticles, polymeric and hyaluronic acid\u2013based carriers, nanocrystals, and porous microsponges, across widely prescribed agents such as simvastatin, atorvastatin, and pitavastatin. Across multiple animal models, nanocarrier-mediated delivery consistently enhances hepatic targeting while attenuating systemic peak exposure, leading to marked reductions in biochemical, histopathological, and functional indicators of skeletal muscle injury relative to conventional formulations. Co-encapsulation strategies incorporating mitochondrial-supportive agents, such as coenzyme Q10 or selenium, further amplify muscle protection while enabling dose reduction. Mechanistically, these protective effects are associated with preservation of mitochondrial respiratory capacity, suppression of reactive oxygen species generation, and attenuation of pro-inflammatory signaling within muscle tissue, pathways directly implicated in muscle degeneration and impaired repair. By integrating molecular mechanisms with translational considerations, this review positions nanocarrier-enabled statin delivery as a promising strategy to decouple lipid-lowering efficacy from muscle toxicity, with broader implications for safeguarding skeletal muscle health and function during chronic pharmacotherapy.<\/jats:p>","DOI":"10.1186\/s41232-026-00413-9","type":"journal-article","created":{"date-parts":[[2026,4,20]],"date-time":"2026-04-20T06:06:07Z","timestamp":1776665167000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Reengineering statin therapy to protect skeletal muscle: nanocarrier strategies for mitigating mitochondrial dysfunction and myotoxicity"],"prefix":"10.1186","volume":"46","author":[{"given":"Obaydah Abd Alkader","family":"Alabrahim","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nageh K.","family":"Allam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2026,4,20]]},"reference":[{"key":"413_CR1","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.mtchem.2017.05.001","volume":"5","author":"DM Ibrahim","year":"2017","unstructured":"Ibrahim DM, Kakarougkas A, Allam NK. 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