Combined Targeted Drug Delivery Systems for Mineral Metabolism Disorders in Chronic Kidney Disease: A Narrative Review.

BACKGROUND: The cardio-renal-bone axis in chronic kidney disease-mineral and bone disorder (CKD-MBD) couples vascular calcification with osteoporosis. Non-specific systemic drug distribution creates a "calcium paradox", where treating one compartment worsens the other. OBJECTIVE: This narrative review evaluates combined targeted drug-delivery systems for CKD-MBD, focusing on mineral metabolism outcomes in vascular and skeletal tissues. METHODS: We searched PubMed, Embase, Web of Science, Cochrane Library, and ClinicalTrials.gov from inception to May 2026. Search terms combined MeSH headings for ("chronic kidney disease" OR "CKD") AND ("nanocarrier" OR "targeted delivery") AND ("vascular calcification" OR "osteoporosis"). Two investigators independently screened titles and abstracts; disagreements were resolved by consensus. Inclusion criteria covered original research or clinical trials on nanocarrier-based delivery for CKD-MBD reporting mineral metabolism outcomes. We excluded conference abstracts, non-CKD mineral disorders, and non-targeted therapy reviews. Risk of bias was assessed using SYRCLE for preclinical studies and the Newcastle-Ottawa Scale for cohorts. Thirty-eight articles met criteria for narrative synthesis; heterogeneity precluded quantitative pooling. RESULTS: Preclinical nanocarrier studies (n=19) show that dual-ligand platforms targeting FGF23/Klotho and TGF-β/Smad pathways attenuate calcification while preserving bone mineralization in animal models. Clinical studies, guidelines, and conventional therapy trials (n=19, N=15,392) indicate that systemic therapies improve biochemical markers but do not halt vascular calcification or fracture risk progression in advanced CKD. No completed human trials of combined targeted delivery for CKD-MBD exist. CONCLUSION: Combined targeted delivery offers a promising investigational strategy to address the calcium paradox. Nonetheless, its clinical value remains unproven; substantial translational work, including Phase I/II safety trials and standardized outcome sets, is required.